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Int. J. Mol. Sci. 2012, 13(7), 9298-9331; doi:10.3390/ijms13079298
Abstract: Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into the mesenchymal lineages of adipocytes, osteocytes and chondrocytes. MSCs can also transdifferentiate and thereby cross lineage barriers, differentiating for example into neurons under certain experimental conditions. MSCs have anti-proliferative, anti-inflammatory and anti-apoptotic effects on neurons. Therefore, MSCs were tested in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), for their effectiveness in modulating the pathogenic process in EAE to develop effective therapies for MS. The data in the literature have shown that MSCs can inhibit the functions of autoreactive T cells in EAE and that this immunomodulation can be neuroprotective. In addition, MSCs can rescue neural cells via a mechanism that is mediated by soluble factors, which provide a suitable environment for neuron regeneration, remyelination and cerebral blood flow improvement. In this review, we discuss the effectiveness of MSCs in modulating the immunopathogenic process and in providing neuroprotection in EAE.
Multiple sclerosis (MS) is a chronic, progressive inflammatory disorder of the central nervous system (CNS). It is characterized by myelin loss, various degrees of axonal pathology, and progressive neurological dysfunction . The associated inflammatory plaque is the pathological hallmark of MS . Experimental autoimmune encephalomyelitis (EAE) is the best-characterized animal model of MS . The finding of inflammatory cells and their secreted molecules in the brain lesions of MS patients and of animals with EAE has supported the widely accepted notion that MS is mediated by pathogenic T cells, which react with myelin antigens, resulting in a larger degeneration of surrounding neurons . These autoreactive T cells then migrate and cross the blood-brain barrier (BBB) to destroy the central neurons and their myelin sheaths as well as their axons.
The exact etiology of MS remains unknown. However, there are three key hypotheses that may explain the causes underlying MS, namely an immune response against the CNS, pathogen trigger and oligodendrocyte degeneration. In addition, genetic factors contribute to MS. Although the pathogenesis of MS is poorly understood, increasing evidence suggests that genetic and environmental factors may both contribute to the development of the disease . Typically, MS affects young adults between 20 and 40 years of age [4,6]. MS shows a strong gender preference, with approximately 70 to 75% of all people with MS being female [4,6]. The incidence and prevalence of MS vary throughout the world, with at least one to two million individuals affected worldwide.
The key morphological characteristic of MS is the demyelination of nerve axons, which blocks or slows signal conduction at the site of demyelination [4,7]. MS patients suffer from a number of neurological symptoms, such as visual problems, changes in sensation, weakness, spasticity, acute/chronic pain, fatigue, depression and paralysis. Neurological symptoms develop when conduction blockade occurs concurrently in a considerable percentage of fibers within a particular neural pathway . During clinical recovery, the inflammation and edema in the CNS resolve, and it is suggested that the restoration of CNS conductivity results from glial ensheathment and remyelination. In contrast, axonal loss is irreversible and may be the basis of neurological dysfunction in chronic MS.
Traditionally, there are four clinical forms of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PR). There is also another form of MS known as clinically isolated syndromes (CIS). These patients present with a single attack of the disease but are not yet diagnosed with MS. The most common form of MS is RRMS, which is associated with acute inflammatory episodes and a reduction in neurological functions . Patients may experience some recovery between relapses, but 80% of RRMS patients progress to SPMS, which is associated with gradual loss of neurological functions and ascending paralysis .
In MS, remyelination and restoration of neuronal functions can be achieved by promoting endogenous mechanisms of neuronal repair or by transplanting exogenous myelinating cells . However, long-term neuronal functional recovery requires regulation of the immunopathogenic process. The current treatments for MS are not completely effective because there is no effective therapy that can inhibit the functions of autoreactive T cells while inducing the remyelination and regeneration processes of neurons and thus prevent disability and irreversible axonal/neuronal damage [9,10]. In addition, there is no effective therapy for MS that can significantly modulate the functions of the cells of the CNS.
The pathogenic process of MS can be divided into inflammatory and degenerative phases. Therefore, to efficiently treat MS, it is necessary to develop a therapy that can specifically regulate the immune responses and that can also induce neuron regeneration. This will provide an effective regimen of immunomodulation and neuroprotection in MS patients. Several studies have shown many lines of evidence of neurodegeneration in MS, including the accumulation of amyloid precursor protein in neurons ; a reduction in the N-acetyl aspartate/creatine ratio, which reflects the degree of disability ; the finding of transected axons, which reflects the degree of inflammation within the active lesions ; damage to mitochondrial DNA and mitochondrial enzyme complexes ; and a reduction in axonal density in the white matter and spinal cords of MS patients [15,16].
Stem cell transplantation is a potential approach that can be used as a therapy to modulate the immunopathogenic process in MS to lead to neuron regeneration and treatment of the disease. Generally, stem cells can differentiate into various cell lineages with the ability to repair damaged tissue by reconstructing the tissue with new cells. The result is a recovery of lost functions, such as nerve conduction in patients with MS. Stem cells can perform their repair function by engrafting into the target tissue or by secreting paracrine factors that can trigger the repair pathways in the damaged tissue. Therefore, the utilization of stem cells in treating MS will rely on their ability to engraft into CNS tissues and then differentiate into neuron-like cells to replace the defective neurons or by secreting molecules that mediate the neuro-repair process in the CNS.
Generally, it is agreed that MSCs, which are derived from adult tissues, can attenuate the encephalitogenic manifestation of MS by suppressing the encephalitogenic T cells that mediate neuronal inflammation and damage [17–28]. The use of MSCs in EAE, the mouse model of MS, has shown that MSCs are able to modulate the immunopathogenesis of EAE and are also able to induce neuroprotection in EAE. Therefore, we will discuss the use of MSCs in EAE mice to investigate their effectiveness in attenuating the encephalitogenic process, possibly by inhibiting the functions of encephalitogenic T cell-mediated neuronal inflammation, neuronal demyelination and axon damage.
2. Experimental Autoimmune Encephalomyelitis (EAE)
The hypothesis that MS is an autoimmune disease was mainly based on the similarities observed between MS and its animal model, EAE. EAE is a demyelinating disease of the CNS that shares similar clinical and pathological features with MS. EAE is induced by immunizing animals with one of the myelin-derived antigens, such as proteolipid protein, myelin oligodendrocyte glycoprotein (MOG), or myelin basic protein (MBP) . EAE is mediated by myelin-specific helper T cells, which are activated in the periphery and then translocate to the CNS, following permeabilization of the BBB [30,31]. Upon entering the CNS, T cells are reactivated by local and infiltrating active antigen presenting cells (APCs), such as dendritic cells, macrophages and microglia, resulting in inflammation and then subsequent neuronal demyelination and axonal damage [30,31].
Depending on the immunization protocol and the background of the mice, EAE can be induced in either an acute chronic progressive form or a relapsing-remitting form . In addition, EAE can be induced by the adoptive transfer of activated myelin-specific helper T cells from EAE mice into naive recipient mice . The EAE model is a useful tool with which to understand the immunopathogenesis of neuronal damage in EAE mice as well as to develop a therapy for MS [34,35].
2.1. Immune Cells in the Experimental Autoimmune Encephalomyelitis (EAE) Model
The inflammation present in MS and in its animal model, EAE, is largely mediated by autoreactive T cells that attack the CNS tissues. Dendritic cells that have been exposed to myelin-derived antigens secrete cytokines that induce the differentiation of naive T cells into effector T cells (Figure 1) in the lymph node. The differentiation of T helper 1 cells requires the presence of interferon-γ (IFN-γ) and IL-12, while IL-4 promotes the development of T helper 2 cells. In the mouse, the differentiation of Th17 cells is promoted by transforming growth factor-β (TGF-β), IL-6 and IL-21, whereas IL-1, IL-6 and IL-23 initiate Th17 differentiation in humans. The differentiation of regulatory T cells (Tregs) requires TGF-β .
However, it is still not clear how the inflammatory response is triggered in MS and EAE. It is possible that myelin antigens trigger the expansion of autoreactive lymphocytes in secondary lymphoid organs of susceptible MS patients and EAE mice. These immune cells then move from lymphoid organs into the circulation . The expansion of inflammatory responses is also enhanced in MS patients and EAE mice due to poor Treg functioning . Then, inflammatory cells adhere to and migrate across the BBB to infiltrate the tissues of the CNS, causing the characteristic inflammatory lesions surrounded by an area of neuronal demyelination and axonal loss . There is evidence to suggest that the pathological heterogeneity in MS lesions is possibly a result of multiple distinct myelin-reactive effector T cells . In addition, it has been noted that cytotoxic T-cells, which are present in MS lesions in significant numbers , may also contribute to tissue damage by attacking oligodendrocytes and by transecting axons [42,43].
2.1.1. T Helper 1 (Th1) and T Helper (Th17) Cells
The inflammatory role of Th1 cells in MS and EAE has been established. It has been reported that Th1 cells secrete inflammatory cytokines in the peripheral blood and in the CNS of affected subjects [44,45]. In addition, microglia activate Th1 cells in the CNS, which in turn activate macrophages to mediate myelin damage through the release of toxic mediators, such as tumor necrosis factor-alpha (TNF-α) . Moreover, the adoptive transfer of myelin-specific CD4+ Th1 cells into naïve recipient mice can induce EAE in these mice [47–54]. Therefore, MS research was primarily based on IFN-γ-producing T cells because myelin-specific CD4+ Th1 cells were sufficient to induce EAE in mice. Several studies have demonstrated that altering IFN-γ production in the myelin-specific T cells prior to their transfer into recipient mice could decrease the encephalitogenic capacity of these CD4+ Th1 cells [52,55,56].
The essential role of IFN-γ in autoimmune encephalomyelitis was further assessed. It was shown that IFNγ-deficient mice were susceptible to EAE, and the disease appeared to be more severe in these mice as compared to control mice [57–59]. This result was further confirmed by using antibodies to neutralize IFN-γ [58,60]. In addition, the number of myelin-specific CD4+ T cells was shown to be increased in IFN-γ-deficient mice . These results suggest that CD4+ Th1 cells can also induce EAE via a mechanism that is independent of IFN-γ. Thus, other cytokines may influence the pathogenic capacity of T cells.
Therefore, the focus of EAE research was shifted to investigations of the role of IL-12 in EAE because it is essential for the differentiation of Th1 cells. The p40 and p35 proteins, which together comprise IL-12, were deleted in mice, and EAE was then evaluated. It was shown that IL-12p40-deficient mice failed to develop EAE; however, EAE was induced in IL-12p35-deficient mice [62,63]. Because IL-12p40 is also a component of IL-23, the role of IL-23 was also evaluated in EAE mice. Because IL-23 also includes the p19 protein, the role of this protein in EAE pathogenesis was also evaluated in EAE mice. Interestingly, IL-12p40- and IL-12p19-deficient mice were resistant to EAE . Accordingly, this result demonstrates that IL-23 and not IL-12 is crucial for the induction of EAE. In addition, IL-23 was found to promote the expansion of myelin-specific IL-17+ T cells, and these IL-17+ T cells were found to induce EAE . Moreover, these Th17 cells produce IL-17, IL-21, IL-9, IL-22 and TNF-α and promote inflammation in EAE [53,65–67]. These findings led to the speculation that myelin-specific Th17 cells were the primary encephalitogenic T cell population in EAE and, possibly, in MS.
Several studies further confirmed the substantial role of Th17 cells in mediating neuronal immunopathogenesis in MS patients and in EAE mice. It has been reported that the number of Th17 cells increases in both the peripheral blood and the brain of MS patients [68,69]. In addition, it was shown that the brain endothelium of MS patients expresses high levels of the IL-17 receptor, and its ligand, IL-17, increases the permeability of the BBB to inflammatory cells . Moreover, recent studies on EAE suggest that the initial inflammatory event in the CNS involves the migration of Th17 cells from the peripheral blood to the spinal fluid . Subsequently, Th17 cells activate the BBB and allow the entry of Th1 cells into the CNS. The blockade of IL-17 was shown to reduce disease severity in EAE [72,73]. In addition, it was demonstrated that the disease severity of EAE was markedly reduced in IL-17-defective mice [74,75]. Moreover, it was reported that Th17 may induce EAE in mice via IL-9 because it was found that the neutralization of IL-9 can attenuate EAE . Furthermore, the Th17 cells that induce EAE in mice were also found to be dependent on IL-1 because IL-1R-defective mice exhibited impaired Th17 cell activity and were also resistant to EAE induction .
Collectively, these studies demonstrated the significant roles of both Th1 and Th17 responses in mediating the immunopathogenesis of MS and its animal model, EAE. Therefore, Th1 and Th17 cells could be potential targets for the development of therapies for MS that modulate the immunopathogenic process to induce neuron regeneration.
2.1.2. T Helper 9 (Th9) Cells
TGF-β and IL-4 induce the development of T helper 9 cells, which produce IL-10 and IL-9 [78,79]. Although Th9 cells produce IL-10, they do not perform immunosuppressive functions. Th9 cells are different from Th1, Th17, and Foxp3-inducible Treg cells . Recently, it was reported that IL-9 contributes to the induction of allergy and asthma . In addition, it was shown that T helper 9 cells can also induce colitis and peripheral neuritis . Moreover, MOG-specific Th9 cells were also shown to induce EAE and peripheral neuritis. Furthermore, IL-9, which is produced by the MOG-specific Th9 cells, can also activate mast cells, which induce demyelination .
2.1.3. γδ T Cells
γδ T cells provide the first line of defense against infection at mucosal sites. γδ T cells directly recognize ligands induced by stress, inflammation or infection. γδ T cells are also involved in both innate and adaptive immunity, and they play a role in both MS and EAE. The detection of γδ T cells in acute MS brain lesions has confirmed their potential role in the neuroimmunopathogenic process in MS . This was further confirmed by the finding of these cells in the cerebrospinal fluid of MS patients . Recently, IL-17 was shown to be produced by γδ T cells during infection [83,84]. In addition, these IL-17-producing γδ T cells were also reported to be present at high frequency in the brains of mice with EAE, and these cells increased the susceptibility of mice to EAE . Thus, these studies confirmed the pathogenic role of γδ T cells in EAE. However, these cells exhibited both protective and pathogenic roles in the EAE model [86–93]. These conflicting results were attributed to the use of different mouse strains and the methods used to deplete γδ T cells.
2.1.4. Regulatory T Cells (Tregs)
Regulatory T cells (Tregs) include natural and inducible Treg cells. Natural Tregs (nTregs) are CD4+ CD25+ T cells, which develop in the thymus and then migrate to the periphery to perform their key role in immune homeostasis [94–96]. Adaptive Tregs, including Tr1, Th3 and various subsets of CD8+ Tregs (as discussed below), are derived in the periphery from naive T cells stimulated by antigen under the influence of the immunosuppressive cytokines IL-10 and TGF-β .
Various types of Treg cells were shown to play crucial roles in the regulation of autoimmune inflammation in MS patients and in EAE mice. It was reported that Tr1 responses and the frequency of nTreg cells are reduced in MS patients [98–101]. In mice, Tregs can control the development and severity of EAE. In addition, it was reported that transgenic mice expressing a T cell receptor specific for myelin antigen develop EAE, whereas non-transgenic CD4+ T cells prevented EAE, suggesting a suppressive role for CD4+ Treg cells [102,103]. Moreover, the transfer of CD4+CD25+ T cells into EAE mice can reduce the severity of the disease .
2.1.5. CD8+ T Cells
Several studies demonstrated that CD8+ T cells have a crucial role in the pathogenesis of MS and EAE. CD8+ T cells were found in significant numbers in MS patients, as well as in EAE mice [41,105,106]. In addition, these cells contribute to tissue damage by attacking oligodendrocytes and by transecting axons [42,43]. However, a regulatory role for CD8+ T cells was also demonstrated in EAE mice. It was demonstrated that EAE is more severe in mice deficient in CD8+ T cells , and distinct subpopulations of CD8+ Treg cells, including CD8+ CD28− and CD8+ CD122+ Treg cells, which can regulate EAE, were also identified [107,108].
Recently, CD8+CD28− regulatory T cells have been characterized in humans. It has been shown for the first time that there is a population of CD8+CD28− suppressor T cells that can suppress the alloreactivity of T helper cells [109–113]. The role of CD8+CD28− regulatory T cells in a chronic model of EAE was also investigated, and it was shown that CD8+ T cells lacking CD28 expression are responsible for the regulatory functions of CD8+ T cells in EAE mice. These regulatory T cells can inhibit the activation of APCs and thus inhibit the activation of the encephalitogenic CD4+ Th1 cells .
The role of CD8+CD122+ regulatory T cells in EAE was also established. CD8+CD122+ regulatory T cells, which produce IL-10, can directly control CD8+ cells by suppressing CD8+ T cell production of IFN-γ, as well as by inhibiting the proliferation of CD8+ T cells [114,115]. It was demonstrated that the depletion of CD122+ cells can increase the duration of EAE symptoms in affected mice, while the transfer of CD8+CD122+ regulatory T cells into EAE mice can dramatically diminish the symptoms in EAE mice, thus demonstrating the protective role of CD8+CD122+ T cells in EAE . In addition, in β2 microglobulin−/− mice, where CD8+ T cells do not develop due to MHC I deficiency, a regulatory role for CD8+ T cells was demonstrated in EAE . Moreover, CD8+ T cells isolated from EAE-recovered mice specifically inhibit MBP-activated CD4+ T-cells in vitro, and their depletion was also followed by recurrence of EAE. The suppressive function of these CD8+ T cells is restricted by the MHC I-like Qa-1 molecule (murine homologue of the human HLA-E), and the adoptive transfer of these cells prevented disease in MBP-immunized mice [117–119]. The failure of resistance to EAE in Qa-1-deficient mice is associated with the escape of Qa-1-deficient CD4+ cells from CD8+ T-cell suppression . The suppressive role of CD8 T cells was further confirmed. It was shown that CD8+ Tregs, which express latency-associated peptide (LAP), can suppress myelin oligodendrocyte glycoprotein-specific immune responses in EAE via a mechanism that requires both IFN-γ and TGF-β . These results provide evidence that CD8+ T cells are important in both inducing resistance to EAE and in abrogating recurrent relapsing episodes of pathogenic autoimmunity in vivo.
These studies demonstrated the essential roles that T cells may play in the immunopathogenesis of MS and its animal model, EAE. Therefore, T cells, including Th1, Th17, Th9, γδ T, CD4 regulatory T cells, CD8 T cells and CD8 regulatory T cells, are potential targets for the development of therapeutic strategies that aim to control T cell mediation of autoimmune processes in the EAE mouse model. Such therapeutic can be further developed into effective treatments for MS. However, recent studies revealed that MS is not only a T cell disease, as B cells were shown to significantly contribute to the disease. An increasing number of reports have demonstrated that B lymphocytes have an important role in the pathogenesis of MS. This includes the presence of B cells, plasma cells, autoantibodies and complement deposition in the blood, CSF and in CNS lesions in the majority of MS patients [122,123]. Most importantly, these autoantibodies contributed to the demyelination process [124–127], and they were reactive against myelin proteins and neurons [128,129]. In addition, a complement-mediated lysis of B cells effectively reduced MS disease activity, thus further confirming the pathogenic role of B cells in MS .
In addition, B cells function as APCs by presenting antigen to helper T cells. It was shown that B cells act as APCs in the periphery in MS patients . Therefore, B cells may support the response of T helper cells in the periphery by activating naïve autoreactive cells and subsequently allowing them to enter the CNS. Thus, B cells may also have a regulatory function through direct contact with T cells. The costimulatory pathway, including CD154-CD40 and CD28-B7, is essential to inhibit the proliferation of T cells through the release of cytokines, such as IL-10 and TGF-β. It was reported that IL-10-producing B cells are deficient in MS patients . Therefore, B cells can be one of the potential targets in MS research for the development of an effective therapy. Simply stated, we can inhibit the functions of naïve T cells via a mechanism that is dependent on the control of B cell functions.
Dendritic cells, which are a group of professional APCs, modulate adaptive immune responses . Generally, inflammatory conditions induce the maturation of dendritic cells, which then induce T cell polarization . Human immature dendritic cells can induce IL-10-producing Tregs and can also induce T-cell anergy . Additionally, regulatory dendritic cells, which have a phenotype different from that of immature DCs, can promote peripheral tolerance and regulatory T cell development . In MS, dendritic cells are among the cells that can infiltrate the CNS . In addition, in SPMS, patients have high numbers of circulating mature dendritic cells compared with RRMS patients . Therefore, dendritic cells are another potential therapeutic target for MS research with regard to the regulation of their functions, which will result in the modulation of the functions of autoreactive T cells, thereby improving or curing the disease.
Macrophages are also important in MS pathogenesis. Perivascular CNS macrophages can be activated by T helper 1 cytokines in MS lesions . Macrophage activation can be either proinflammatory or anti-inflammatory, depending on the cytokine exposure. Macrophages exposed to IFN-γ are classified as proinflammatory M1 macrophages and are likely to contribute to myelin damage by phagocytosis and the release of neurotoxic mediators. Myelin- and neuroantigen-containing APCs were described in the cervical lymph nodes of healthy individuals, and these CNS antigen-containing APCs are increased in MS patients. These data suggest that myelin and neuronal antigens released from damaged CNS tissue may be captured by the CNS APCs and migrate into the cervical lymph nodes. Interestingly, neuronal antigens are presented by proinflammatory APCs, whereas myelin antigens are presented by anti-inflammatory APCs. Thus, pathogenic and regulatory CNS-specific T cells may be differentiated in the cervical lymph nodes . These data provide another therapeutic pathway that can be pursued in the development of MS treatment. The modulation of macrophage functions would aid in regulating the autoimmune response of T cells, which would offer direct or indirect suppressive mechanisms by which to control the autoimmune responses and neuronal damage in MS patients.
Clearly, B cells, dendritic cells and macrophages can all contribute to the pathogenesis of MS; therefore, they are potential targets that should be pursued to develop effective therapies for MS. However, there is limited information regarding the modulating effects of MSCs on the functions of B cells, dendritic cells and macrophages in EAE. Therefore, our focus in this review will be on the effectiveness of MSCs in attenuating the encephalitogenic manifestation of EAE by suppressing the functions of the autoreactive T cells that mediate neuronal inflammation and damage.
3. Mesenchymal Stem Cells (MSCs)
Stem cells are specialized cells that are capable of self-renewal and multilineage differentiation. They fall into the two broad categories of embryonic stem cells (ESCs) and adult stem cells (ASCs). ESCs are pluripotent and differentiate into cell derivatives of the three germ layers: endoderm, ectoderm and mesoderm. ESCs are derived from the inner cell mass of the blastocyst; therefore, their use in cell-based therapy is controversial because of blastocyst destruction [140–143]. In contrast, the use of ASCs in cell-based therapy is less controversial because they are obtainable from a wide range of tissues, such as bone marrow, adipose tissue, placenta and umbilical cord. One important subset of ASCs is MSCs, which are multipotent cells that differentiate into mesenchymal cell lineages, including adipocytes, osteocytes, chondrocytes and myocytes [144,145]. However, MSCs can “transdifferentiate” and thereby cross lineage barriers, differentiating into different cell types, such as neurons (see below).
Mesenchymal stem cells have immunosuppressive properties that make them a therapeutic option that can be used to modulate the immunopathogenesis of multiple sclerosis and its animal model, EAE. Therefore, the effectiveness of MSCs in attenuating the encephalitogenic manifestation of EAE by suppressing the functions of the autoreactive T cells that mediate neuronal inflammation and damage has been examined.
Immunosuppressive Characteristics of Mesenchymal Stem Cells
Several studies have confirmed the immunosuppressive characteristics of MSCs. It was found that MSCs express MHC-I but lack the expression of MHC-II and costimulatory molecules [146–161]. In addition, MSCs suppress the immune responses of allogeneic lymphocytes [162,163]. In a mixed lymphocyte reaction, baboon or human bone marrow derived MSCs (BMMSCs) can inhibit the proliferation of allogeneic lymphocytes (Figure 2) [162,163]. In addition, human BMMSCs can also suppress the proliferative functions of T cells stimulated by antibodies to CD3 or CD28 . Moreover, murine and human BMMSCs can inhibit the proliferation of lymphocytes stimulated with anti-CD3, IL2, IL7 or IL15 in vitro [165,166]. This inhibitory effect was shown to be partially mediated by IFN-γ . Similarly, human placental MSCs and amniotic membrane MSCs can suppress the proliferation of allogeneic lymphocytes [146,148,149,167–170]. Furthermore, fetal liver MSCs can inhibit mitogen-stimulated lymphocytes [171,172], and it was similarly demonstrated that adipose-derived MSCs can inhibit T cell proliferation . Moreover, it was shown that dental pulp MSCs (DP-MSCs) can suppress the proliferation of peripheral blood mononuclear cells . Collectively, these studies showed that MSCs derived from different sources are immunosuppressive through the inhibition of the proliferation of allogeneic lymphocytes.
In addition, it was shown that MSCs can modulate the functions of both T and B lymphocytes. MSCs can inhibit the production of TNF-α and IFN-γ by CD4+ T and CD8+ T cells, whereas they can upregulate the expression of IL-10 and restore the secretion of IL-4 by CD4+ and CD8+ T cells  (Figure 2). In addition, fetal liver MSCs can down-regulate the production of IFN-γ and can increase the secretion of IL-10 in stimulated T cells . Similarly, it was reported that MSCs derived from adipose tissues can enhance the secretion of IL-4, IL-5, and IL-10 by T cells . In contact cultures, human MSCs were shown to suppress the ex vivo expansion of γδ T cells without modulating their cytotoxic function .
In addition, BMMSCs were found to selectively suppress the proliferative activities of both T and B lymphocytes via a mechanism that is mediated by programmed death 1 inhibitory molecule (PD-1) and its ligands PD ligand-1 (PD-L1) and PD ligand-2 (PD-L2) [175,176]. Moreover, BMMSCs can suppress the immune function of B cells stimulated by anti-CD40 or IL-4 . This inhibitory effect of BMMSCs on B cells was also confirmed in other studies. It was shown that human BMMSCs can suppress the proliferation, differentiation and chemotactic activities of B cells [178,179]. Similarly, human placental MSCs can also suppress the immune responses of different populations of immune cells, including CD4+ and CD8+ T cells .
CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are effector cells with cytotoxic activities that can eliminate cancer or infected cells. CTLs are stimulated following their interaction with antigenic peptides expressed on MHC class I molecules. Human BMMSCs are recognized as targets by pre-stimulated alloreactive CTLs, and they can suppress the differentiation of CTL precursors into CTL effectors through the secretion of suppressive factors [180,181].
NK cells that are constitutively cytotoxic against allogeneic cells cannot lyse MSCs [148,181]. However, NK cells that are stimulated with IL-2 can lyse MSCs [182,183]. In addition, NK cells stimulated with IL-2 and IL-15 can lyse MSCs . Therefore, these data on the ability of NK cells to lyse MSCs are contradictory. In addition, a recent study showed that CD8+ T and NK cells can lyse allogeneic MSCs . Therefore, more research is necessary to study the susceptibility of MSCs to lysis by immune cells because this knowledge is indispensable for the development of an effective and safe MSC therapy. However, it is possible that MSCs have a transient effect on the inflammatory milieu in graft versus host disease (GVHD) because it was shown that MSCs can have long-lasting effects by passing on some of their effects to other cell types, such as regulatory T-cells [186,187]. Thus, this result indicates that the long-term effectiveness of MSCs would not be diminished if MSCs are lysed soon after infusion.
In addition, human BMMSCs can inhibit the proliferation of NK cells and the cytolytic activity of NK cells . Moreover, Human BMMSCs can inhibit the production of IFN-γ by NK cells . However, another study showed that human BMMSCs can significantly increase the secretion of IFN-γ by NK cells . This inconsistency was attributed to the different effects that MSCs could have on NK cells. This possibility may depend on whether NK cells are triggered by IL-2 . Another possibility is that the ratios of NK cells to MSCs used in different experimental settings may have differential activating or inhibitory effects on NK cells by MSCs. It is difficult to determine in vivo whether one or many NK cells interact simultaneously with an individual stem cell or vice versa.
Regarding the mechanism underlying the immunosuppressive function of MSCs, several reports suggest that cell-cell contact is not a compulsory requirement for the suppression of immune cell functions by MSCs [189–191]. Therefore, MSCs must produce soluble factors that mediate their immunosuppressive functions on immune cells. Several soluble factors were detected in the culture medium of MSCs, including stem cell factor (SCF), IL-6, IL-8, IL-10, IL-12, IFN-γ, PGE2 (prostaglandin E2), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), hepatocyte growth factor (HGF) and transforming growth factor -β1 (TGF-β1) [146,161,188,192,193].
The immunosuppressive capacity of MSCs in vivo was also confirmed in various studies . It was reported that the intravenous injection of MSCs can prolong the survival of an allogeneic skin graft in baboons . Likewise, the injection of murine BMMSCs into mice can stimulate the survival of allogeneic skin grafts in mice . In addition, it was shown that MSCs were not rejected following their transplantation into allogeneic immunocompetent mice . However, the subcutaneous injection of melanoma cells resulted in tumor growth in allogeneic recipients only when MSCs were co-injected . Although the possible side effects of immunosuppression induced by MSCs need to be investigated in more detail, the effectiveness of MSCs for many therapeutic applications remains of great interest. Recently, it was revealed that the injection of mouse MSCs prolonged the survival of skin transplants in mice . In addition, the immunosuppressive effect of human MSCs on the severity of bleomycin-induced inflammation and fibrosis in an animal model was evaluated. The presence of transplanted MSCs reduced the neutrophil infiltration and significantly decreased the inflammation, as well as the severity of lung fibrosis, in mice treated with allogeneic or xenogeneic placenta-derived cells .
The therapeutic efficacy of MSCs in the murine model of MS, EAE, was also reported (see below). In addition, the intravenous injection of baboons with autologous or allogeneic baboon MSCs together with hematopoietic progenitor cells facilitated a faster hematopoietic recovery . This result was further confirmed by a recent study showing that allogeneic BMMSCs can reduce the severity of GVHD in an F1 model of acute GVHD .
Therefore, the immunosuppressive features of MSCs, together with their ability to differentiate into neuronal lineages, support the use of MSCs in EAE to modulate the immunopathogenic process underlying the neuronal damage, as well as to offer neuroprotection in EAE, to develop therapeutic strategies for MS.
4. The Use of MSCs in Clinical Experimental Autoimmune Encephalomyelitis (EAE)
4.1. Immune Modulatory Effect of MSCs in EAE
Several studies showed that MSCs exert immunoinhibitory functions on immune cells in vitro and in vivo . These characteristics, together with the ability of MSCs to differentiate into neuron-like cells  and migrate to the CNS , promoted the use of MSCs in EAE treatment. Several studies confirmed the differentiation of MSCs into neurons. Rat and human BMMSCs were shown to differentiate into neurons in vitro [201,202]. The differentiated cells expressed a variety of neuron-specific markers, including neuron-specific enolase, tau, neurofilament M, neuron-specific nuclear protein, β-III-tubulin, and synaptophysin [202,203]. Pioneering studies also demonstrated the differentiation of BMMSCs into neural cell types in vivo. The transplantation of MSCs into mouse ventricles or striatum resulted in their expression of astrocytic traits [199,204]. It was shown for the first time that after the injection of mouse BMMSCs into the lateral ventricle of neonatal mice, MSCs migrated throughout the forebrain and cerebellum and differentiated into astrocytes in the striatum, the hippocampus and the reticular formation of the brain stem . In addition, MSCs were found within neuron-rich regions and within the cerebellum . The differentiation of MSCs into neurons was further confirmed in a study of the differentiation of mouse BMMSCs into phenotypic neural cells in ischemic animals . Similarly, human BMMSCs implanted into ischemic rats, increased neurogenesis in these rats . In addition, it was shown that human BMMSCs can differentiate into neural cells following their implantation in the brain of ischemic rats . Moreover, the differentiation of MSCs into neurons was also demonstrated in the embryonic rat brain , and the stereotactic implantation of mouse MSCs into the brain of rats demonstrated the differentiation of implanted MSCs into mature neurons . Recently, the transplantation of human placental MSCs into the striatum in a rat model of Parkinson’s disease also confirmed the ability of MSCs to differentiate into neurons . Collectively, these studies support the ability of MSCs to differentiate into neurons.
The ability of BMMSCs to modulate the immunopathogenic process, leading to neuroprotection in EAE, was also demonstrated in several studies. It was shown that BMMSCs can improve neuronal recovery in EAE, possibly by stimulating oligodendrogenesis and reducing the inflammatory infiltrates, demyelination and axonal loss in the CNS of EAE mice by inhibiting autoreactive T cell responses [20,28,211,212]. In addition, the accumulation of BMMSCs in the tissues of the CNS and lymphoid organs of EAE mice reduced the severity of the disease by modulating the functions of T cells, as demonstrated by the following: (1) decreased inflammatory cytokine (INF-γ and IL-17) secretion by Th1 and Th17 cells; (2) increased numbers of Th2 cells and regulatory T cells and their secretion of anti-inflammatory cytokines; (3) decreased numbers of Th1 and Th17 T cells; and (4) increased numbers of oligodendrocytes in the CNS tissues of EAE mice (Figure 3) [17,21,26,27,213].
The neuroprotective effect of MSCs in EAE mice was further confirmed. It was shown that the administration of MSCs to EAE mice suppressed the clinicopathological manifestations of EAE and prevented axonal damage . In this study, intraventricularly injected BMMSCs were detected in the inflamed CNS tissues of the EAE mice, and these MSCs exhibited features of neuronal lineages . In addition, the intravenously injected MSCs migrated to the lymph nodes, which were associated with immunomodulatory effects, as demonstrated by the decrease in the immune cell infiltrate in the CNS . Other studies confirmed the neuroprotective property of MSCs. The treatment of EAE mice with human endometrial MSCs significantly reduced EAE manifestations as a result of a reduction in Th1 and Th17 cell infiltrates in the CNS tissues of EAE mice . This reduction in the target organ was probably a result of MSC-induced regulatory mechanisms in the periphery, as demonstrated by the up-regulation of IL-10, IL-27, immune suppressive enzyme, indoleamine-2,3-dioxygenase (IDO), and Foxp3 expression, thus indicating a higher percentage of putative Tregs . In addition, BMMSCs that were transplanted intracerebroventricularly into EAE mice delayed the onset of symptoms and increased animal survival via mechanisms that possibly involved both immunomodulation and neuroprotection .
Recently, it was shown that with the intravenous administration of adipose-derived MSCs to EAE mice before disease onset, MSCs homed into lymphoid organs and migrated inside the CNS. These MSCs reduced the severity of EAE by immune modulation and decreased spinal cord inflammation and demyelination . In addition, the administration of these adipose-derived MSCs to animals with chronic EAE ameliorated the disease course and reduced both demyelination and axonal loss while inducing Th2-type cytokine production . Moreover, the infiltration of these MSCs within demyelinated areas was accompanied by increased numbers of endogenous oligodendrocyte progenitors . The potential neuroprotective role of MSCs in EAE mice was also further confirmed. It was shown that human BMMSCs can migrate into the spinal cord in mice with EAE and that this significantly reduced the clinical disease severity . The injected MSCs accumulated in the demyelinated areas, and these cells expressed neural markers . In addition, the number of spinal cord white matter lesions and areas of white matter demyelination were reduced and were associated with decreased inflammatory infiltration after treatment with MSCs . A recent study further confirmed the modulatory effects of MSCs on the immunopathogenic process in EAE. The transplantation of human placental MSCs into EAE mice yielded a decrease in disease severity in the transplanted animals via a mechanism that depends on the anti-inflammatory protein TNF-α-stimulated gene/protein 6 (TSG-6) .
These results demonstrate that MSCs have the therapeutic potential of suppressing the autoimmune response in early phases of disease and of inducing local neuroregeneration by endogenous progenitors in animals with established disease. In addition, MSCs were also shown to ameliorate the disease severity in EAE mice by the secretion of PGE2, which is dependent upon IDO for its immunosuppressive function . The role of soluble factors in modulating the pathogenesis of EAE was confirmed in a recent study demonstrating that conditioned medium from human MSCs can reduce the functional deficits in EAE mice and can also promote the development of oligodendrocytes and neurons . In agreement with this finding, it was found that human BMMSCs produce soluble factors that are important for mediating axon outgrowth and recovery in rats with injured spinal cords . In addition, it was shown that BMMSCs can induce oligodendrocyte differentiation via factors produced by MSCs . Moreover, when neural progenitor cells (NPCs), which were pre-differentiated in vitro by MSC-derived soluble factors, were transplanted in situ together with MSCs into hippocampal slice cultures, the grafted NPCs survived, and the majority of them differentiated into oligodendrocytes and neural progenitors . Therefore, there is a general agreement regarding the effects of MSCs on improving the clinical manifestations of EAE in mice. However, the immunomodulatory properties of MSCs are not the only mechanisms that could explain their therapeutic plasticity. MSCs express a broad spectrum of regulatory proteins that may mediate their therapeutic functions. In addition, the ability of MSCs to respond to injuries depends on their microenvironment, regardless of whether they have a low engraftment rate in vivo . MSCs produce cytokines and a variety of soluble factors that regulate several biological activities . This suggests that MSCs can promote the survival of other cells and thus play a major role in the maintenance of tissue homeostasis .
4.2. Neuroprotective Properties of MSCs
The ability of MSCs to home to injured tissues and to transdifferentiate into multiple cell types in vivo was disputed by recent observations demonstrating that only small numbers of the injected MSCs can engraft into tissues and that the supernatant of MSC culture is sufficient to block hepatic failure [224,225]. In addition, several in vitro studies demonstrated that MSCs exert significant biological effects on target cells without the need for cell contact. Therefore, these and other in vitro and in vivo studies generated the hypothesis that the therapeutic effects of MSCs depend significantly on soluble factors secreted by MSCs and that these factors may mediate the MSC induction of tissue repair.
A number of in vitro studies showed that MSCs have the potential to rescue neurons from apoptosis [226–228]. Thus, this anti-apoptotic function of MSCs, together with their immunomodulatory properties, explain the reduction in axonal loss observed in EAE mice treated with MSCs [20,23,212]. In addition, MSCs secrete neurotrophic molecules, which would further explain how MSCs can induce remyelination in EAE mice [18,211,229].
The neuroprotective property of MSCs in EAE as discussed above was supported by several studies utilizing experimental models of stroke and spinal cord injury. For example, after the direct injection of BMMSCs into demyelinated spinal cords, they promoted remyelination . In another study involving the transplantation of MSCs into the subarachnoid space of the lumbar spine, the MSCs infiltrated into the spinal cord parenchyma and then differentiated into immature neurons or glial cells. This was followed by complete transection and motor improvement . In addition, BMMSCs were shown to improve the survival of motor neurons following their transplantation into the lumbar spinal cord in an animal model of human amyotrophic lateral sclerosis .
In a model of stroke, the intravenous administration of MSCs increased the expression of basic fibroblast growth factor, reduced apoptosis, promoted endogenous neurogenesis, and improved functional recovery . MSCs can directly promote the plasticity of damaged neurons or stimulate glial cells to secrete neurotrophins (e.g., brain-derived neurotrophic factor (bDNF) and nerve growth factor (NGF)), reduce apoptosis in the penumbral zone of the lesion and support the proliferation of the endogenous cells in the subventricular zone . In addition, the implantation of BMMSCs in the hippocampus of immunodeficient mice stimulated the proliferation, migration and differentiation of the endogenous neural stem cells, which survived as differentiated neural cells via their secretion of various trophic factors, including NGF, vascular endothelial growth factor (VEGF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (FGF-2) and BMI-1 .
This indirect effect of MSCs on the improvement of neurogenesis was further supported in a mouse model of global ischemia, where MSCs improved neurological function and prevented neuronal cell death in the hippocampus via a mechanism that was mediated by the local microglia, which expressed high levels of neuroprotective factors, such as insulin-like growth factor 1 (IGF-1) . This neuroprotective effect of MSCs on microglia was further confirmed. It was shown that MSCs can inhibit the production of inflammatory factors, including nitric oxide (NO), tumor necrosis factor, IL1-β and reactive oxygen species (ROS), by activated microglia, thus preventing neuronal damage via the production of neurotrophic factors, which are likely to be involved in neuroprotection . In agreement with these results, it was reported that the cell death of dopaminergic neurons induced by activated microglia can be inhibited by MSCs [220,238]. In addition to the neuroprotective effects of MSCs on activated microglia, MSCs can significantly inhibit the up-regulation of molecules involved in oxyradical detoxification occurring in EAE . Similarly, MSCs can resolve the increase of oxidative stress-associated proteins in neurons exposed to H2O2 . This result suggests that MSCs can inhibit the neuroinflammatory process that is mediated by proinflammatory and oxidative stress molecules secreted by macrophages and microglia. However, microglia are not the only neural cell type targeted by MSCs; it was shown that MSCs can also inhibit the differentiation of neural precursor cells (NPCs) into astrocytes in vitro [220,229].
MSC transplantation represents an attractive therapeutic approach for MS treatment. However, many questions are essential to be answered before the use of MSCs in MS patients to determine their therapeutic potential. For example, it is essential to know the effect of ageing on MSC biology, since several studies indicate that ageing can affect the proliferation and differentiation capacities of MSCs. It has been shown that MSCs undergo replicative senescence, loss of differentiation capacity and ultimate growth arrest with increasing time in culture [240–250]. However, another study showed that aged MSCs have a higher proliferation rate than young MSCs  while another study did not find differences in the proliferation potential between aged and young MSCs . These controversial results were attributed to species, gender and donor age of animals used in these studies and also to differences in the conditions of cell culture. However, these studies suggest that aging may change but not block the proliferation of MSCs. Regarding the differentiation potential of MSCs, the majority of studies reported an age-related reduction in the osteogenic potential [244,246,249–251]. In addition, this decrease in osteogenic capacity was associated with increased ability of aged MSCs to differentiate into adipocytes . Since, these studies demonstrated that aging has an effect on the biological behaviours of MSCs following their long expansion time in culture; therefore this would not prevent their use in cell based therapies. More studies are necessary in order to determine the effects of aging on the immune- suppressive and neuroprotection functions of MSCs in vitro and in vivo before the use of MSCs in MS patients. It would be essential to compare the capacity of young versus aged MSCs in providing neuroprotection and neuroregeneration effects in EAE mice.
Evidence is increasing in support of the use of MSCs in treating neurological diseases, such as MS, via modulating the immunopathogenic process and promoting the repair of damaged neurons. In addition, the current data available in the literature suggest that the neurotherapeutic effect of MSCs is possibly mediated via a direct contact between MSCs and damaged neuronal cells or via soluble factors that are secreted by MSCs. MSCs secrete anti-inflammatory, anti-apoptotic and neurotrophic factors. These soluble factors can induce protective phenotypic features in other cells, such as microglia, and can also induce the remyelination process, thus maintaining the neuroprotective effects observed in experimental animal models of MS and other neurological disorder models. Therefore, these immunomodulatory and protective properties of MSCs may provide the basis to translate the neurotherapeutic effects of MSCs seen in animal models into humans in well-designed and carefully controlled clinical studies.
We wish to acknowledge the financial support from KAIMRC Grant No. RC08/114 and KACST Grant No. ARP-29-186.
- Conflict of InterestThe authors have no conflicts of interest to declare.
- Noseworthy, J.H.; Lucchinetti, C.; Rodriguez, M.; Weinshenker, B.G. Multiple sclerosis. N. Engl. J. Med 2000, 343, 938–952. [Google Scholar]
- Frohman, E.M.; Racke, M.K.; Raine, C.S. Multiple sclerosis—The plaque and its pathogenesis. N. Engl. J. Med 2006, 354, 942–955. [Google Scholar]
- Martin, R. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis and their application for new therapeutic strategies. J. Neural Transm. Suppl 1997, 49, 53–67. [Google Scholar]
- Compston, A.; Coles, A. Multiple sclerosis. Lancet 2008, 372, 1502–1517. [Google Scholar]
- Ebers, G.C. Environmental factors and multiple sclerosis. Lancet Neurol 2008, 7, 268–277. [Google Scholar]
- Duquette, P.; Pleines, J.; Girard, M.; Charest, L.; Senecal-Quevillon, M.; Masse, C. The increased susceptibility of women to multiple sclerosis. Can. J. Neurol. Sci 1992, 19, 466–471. [Google Scholar]
- McDonald, W.I.; Sears, T.A. The effects of experimental demyelination on conduction in the central nervous system. Brain 1970, 93, 583–598. [Google Scholar]
- Kuehn, B.M. Scientists probe strategies to repair neuron damage in multiple sclerosis. J. Am. Med. Assoc 2011, 305. [Google Scholar]
- Karussis, D.; Grigoriadis, S.; Polyzoidou, E.; Grigoriadis, N.; Slavin, S.; Abramsky, O. Neuroprotection in multiple sclerosis. Clin. Neurol. Neurosurg 2006, 108, 250–254. [Google Scholar]
- Steinman, L. Multiple sclerosis: A two-stage disease. Nat. Immunol 2001, 2, 762–764. [Google Scholar]
- Gehrmann, J.; Banati, R.B.; Cuzner, M.L.; Kreutzberg, G.W.; Newcombe, J. Amyloid precursor protein (APP) expression in multiple sclerosis lesions. Glia 1995, 15, 141–151. [Google Scholar]
- Foong, J.; Rozewicz, L.; Davie, C.A.; Thompson, A.J.; Miller, D.H.; Ron, M.A. Correlates of executive function in multiple sclerosis: The use of magnetic resonance spectroscopy as an index of focal pathology. J. Neuropsychiatry Clin. Neurosci 1999, 11, 45–50. [Google Scholar]
- Trapp, B.D.; Peterson, J.; Ransohoff, R.M.; Rudick, R.; Mork, S.; Bo, L. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med 1998, 338, 278–285. [Google Scholar]
- Vladimirova, O.; O’Connor, J.; Cahill, A.; Alder, H.; Butunoi, C.; Kalman, B. Oxidative damage to DNA in plaques of MS brains. Mult. Scler 1998, 4, 413–418. [Google Scholar]
- Lovas, G.; Szilagyi, N.; Majtenyi, K.; Palkovits, M.; Komoly, S. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 2000, 123, 308–317. [Google Scholar]
- Evangelou, N.; Esiri, M.M.; Smith, S.; Palace, J.; Matthews, P.M. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann. Neurol 2000, 47, 391–395. [Google Scholar]
- Bai, L.; Lennon, D.P.; Eaton, V.; Maier, K.; Caplan, A.I.; Miller, S.D.; Miller, R.H. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009, 57, 1192–1203. [Google Scholar]
- Constantin, G.; Marconi, S.; Rossi, B.; Angiari, S.; Calderan, L.; Anghileri, E.; Gini, B.; Bach, S.D.; Martinello, M.; Bifari, F.; et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem. Cells 2009, 27, 2624–2635. [Google Scholar]
- Einstein, O.; Grigoriadis, N.; Mizrachi-Kol, R.; Reinhartz, E.; Polyzoidou, E.; Lavon, I.; Milonas, I.; Karussis, D.; Abramsky, O.; Ben-Hur, T. Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis. Exp. Neurol 2006, 198, 275–284. [Google Scholar]
- Gerdoni, E.; Gallo, B.; Casazza, S.; Musio, S.; Bonanni, I.; Pedemonte, E.; Mantegazza, R.; Frassoni, F.; Mancardi, G.; Pedotti, R.; et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann. Neurol 2007, 61, 219–227. [Google Scholar]
- Grigoriadis, N.; Lourbopoulos, A.; Lagoudaki, R.; Frischer, J.M.; Polyzoidou, E.; Touloumi, O.; Simeonidou, C.; Deretzi, G.; Kountouras, J.; Spandou, E.; et al. Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis. Exp. Neurol 2011, 230, 78–89. [Google Scholar]
- Karussis, D.; Kassis, I.; Kurkalli, B.G.; Slavin, S. Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): A proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. J. Neurol. Sci 2008, 265, 131–135. [Google Scholar]
- Kassis, I.; Grigoriadis, N.; Gowda-Kurkalli, B.; Mizrachi-Kol, R.; Ben-Hur, T.; Slavin, S.; Abramsky, O.; Karussis, D. Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch. Neurol 2008, 65, 753–761. [Google Scholar]
- Lu, Z.; Hu, X.; Zhu, C.; Wang, D.; Zheng, X.; Liu, Q. Overexpression of CNTF in Mesenchymal Stem Cells reduces demyelination and induces clinical recovery in experimental autoimmune encephalomyelitis mice. J. Neuroimmunol 2009, 206, 58–69. [Google Scholar]
- Matysiak, M.; Orlowski, W.; Fortak-Michalska, M.; Jurewicz, A.; Selmaj, K. Immunoregulatory function of bone marrow mesenchymal stem cells in EAE depends on their differentiation state and secretion of PGE2. J. Neuroimmunol 2011, 233, 106–111. [Google Scholar]
- Rafei, M.; Birman, E.; Forner, K.; Galipeau, J. Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. Mol. Ther 2009, 17, 1799–1803. [Google Scholar]
- Rafei, M.; Campeau, P.M.; Aguilar-Mahecha, A.; Buchanan, M.; Williams, P.; Birman, E.; Yuan, S.; Young, Y.K.; Boivin, M.N.; Forner, K.; et al. Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J. Immunol 2009, 182, 5994–6002. [Google Scholar]
- Zappia, E.; Casazza, S.; Pedemonte, E.; Benvenuto, F.; Bonanni, I.; Gerdoni, E.; Giunti, D.; Ceravolo, A.; Cazzanti, F.; Frassoni, F.; et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005, 106, 1755–1761. [Google Scholar]
- Stromnes, I.M.; Goverman, J.M. Active induction of experimental allergic encephalomyelitis. Nat. Protoc 2006, 1, 1810–1819. [Google Scholar]
- Furtado, G.C.; Marcondes, M.C.; Latkowski, J.A.; Tsai, J.; Wensky, A.; Lafaille, J.J. Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J. Immunol 2008, 181, 4648–4655. [Google Scholar]
- O’Connor, R.A.; Prendergast, C.T.; Sabatos, C.A.; Lau, C.W.; Leech, M.D.; Wraith, D.C.; Anderton, S.M. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol 2008, 181, 3750–3754. [Google Scholar]
- Steinman, L. Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999, 24, 511–514. [Google Scholar]
- Stromnes, I.M.; Goverman, J.M. Passive induction of experimental allergic encephalomyelitis. Nat. Protoc 2006, 1, 1952–1960. [Google Scholar]
- Teitelbaum, D.; Meshorer, A.; Hirshfeld, T.; Arnon, R.; Sela, M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur. J. Immunol 1971, 1, 242–248. [Google Scholar]
- Yednock, T.A.; Cannon, C.; Fritz, L.C.; Sanchez-Madrid, F.; Steinman, L.; Karin, N. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 1992, 356, 63–66. [Google Scholar]
- Sakaguchi, S.; Powrie, F. Emerging challenges in regulatory T cell function and biology. Science 2007, 317, 627–629. [Google Scholar]
- Lopez-Diego, R.S.; Weiner, H.L. Novel therapeutic strategies for multiple sclerosis—A multifaceted adversary. Nat. Rev. Drug Discov 2008, 7, 909–925. [Google Scholar]
- Viglietta, V.; Baecher-Allan, C.; Weiner, H.L.; Hafler, D.A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med 2004, 199, 971–979. [Google Scholar]
- Leussink, V.I.; Zettl, U.K.; Jander, S.; Pepinsky, R.B.; Lobb, R.R.; Stoll, G.; Toyka, K.V.; Gold, R. Blockade of signaling via the very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) causes increased T cell apoptosis in experimental autoimmune neuritis. Acta Neuropathol 2002, 103, 131–136. [Google Scholar]
- Jager, A.; Dardalhon, V.; Sobel, R.A.; Bettelli, E.; Kuchroo, V.K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol 2009, 183, 7169–7177. [Google Scholar]
- Skulina, C.; Schmidt, S.; Dornmair, K.; Babbe, H.; Roers, A.; Rajewsky, K.; Wekerle, H.; Hohlfeld, R.; Goebels, N. Multiple sclerosis: Brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc. Natl. Acad. Sci. USA 2004, 101, 2428–2433. [Google Scholar]
- Medana, I.; Martinic, M.A.; Wekerle, H.; Neumann, H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol 2001, 159, 809–815. [Google Scholar]
- Giuliani, F.; Goodyer, C.G.; Antel, J.P.; Yong, V.W. Vulnerability of human neurons to T cell-mediated cytotoxicity. J. Immunol 2003, 171, 368–379. [Google Scholar]
- Chitnis, T. The role of CD4 T cells in the pathogenesis of multiple sclerosis. Int. Rev. Neurobiol 2007, 79, 43–72. [Google Scholar]
- Hedegaard, C.J.; Krakauer, M.; Bendtzen, K.; Lund, H.; Sellebjerg, F.; Nielsen, C.H. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology 2008, 125, 161–169. [Google Scholar]
- Delgado, S.; Sheremata, W.A. The role of CD4+ T-cells in the development of MS. Neurol. Res 2006, 28, 245–249. [Google Scholar]
- Pettinelli, C.B.; McFarlin, D.E. Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: Requirement for Lyt 1+ 2- T lymphocytes. J. Immunol 1981, 127, 1420–1423. [Google Scholar]
- McDonald, A.H.; Swanborg, R.H. Antigen-specific inhibition of immune interferon production by suppressor cells of autoimmune encephalomyelitis. J. Immunol 1988, 140, 1132–1138. [Google Scholar]
- Ando, D.G.; Clayton, J.; Kono, D.; Urban, J.L.; Sercarz, E.E. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol 1989, 124, 132–143. [Google Scholar]
- Waldburger, K.E.; Hastings, R.C.; Schaub, R.G.; Goldman, S.J.; Leonard, J.P. Adoptive transfer of experimental allergic encephalomyelitis after in vitro treatment with recombinant murine interleukin-12. Preferential expansion of interferon-gamma-producing cells and increased expression of macrophage-associated inducible nitric oxide synthase as immunomodulatory mechanisms. Am. J. Pathol 1996, 148, 375–382. [Google Scholar]
- Yura, M.; Takahashi, I.; Serada, M.; Koshio, T.; Nakagami, K.; Yuki, Y.; Kiyono, H. Role of MOG-stimulated Th1 type “light up” (GFP+) CD4+ T cells for the development of experimental autoimmune encephalomyelitis (EAE). J. Autoimmun 2001, 17, 17–25. [Google Scholar]
- Lovett-Racke, A.E.; Rocchini, A.E.; Choy, J.; Northrop, S.C.; Hussain, R.Z.; Ratts, R.B.; Sikder, D.; Racke, M.K. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immunity 2004, 21, 719–731. [Google Scholar]
- Gocke, A.R.; Cravens, P.D.; Ben, L.H.; Hussain, R.Z.; Northrop, S.C.; Racke, M.K.; Lovett-Racke, A.E. T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. J. Immunol 2007, 178, 1341–1348. [Google Scholar]
- Hemmer, B.; Cepok, S.; Zhou, D.; Sommer, N. Multiple sclerosis—A coordinated immune attack across the blood brain barrier. Curr. Neurovasc. Res 2004, 1, 141–150. [Google Scholar]
- Racke, M.K.; Bonomo, A.; Scott, D.E.; Cannella, B.; Levine, A.; Raine, C.S.; Shevach, E.M.; Rocken, M. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. Exp. Med 1994, 180, 1961–1966. [Google Scholar]
- Racke, M.K.; Burnett, D.; Pak, S.H.; Albert, P.S.; Cannella, B.; Raine, C.S.; McFarlin, D.E.; Scott, D.E. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J. Immunol 1995, 154, 450–458. [Google Scholar]
- Willenborg, D.O.; Fordham, S.; Bernard, C.C.; Cowden, W.B.; Ramshaw, I.A. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol 1996, 157, 3223–3227. [Google Scholar]
- Lublin, F.D.; Knobler, R.L.; Kalman, B.; Goldhaber, M.; Marini, J.; Perrault, M.; D’Imperio, C.; Joseph, J.; Alkan, S.S.; Korngold, R. Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 1993, 16, 267–274. [Google Scholar]
- Ferber, I.A.; Brocke, S.; Taylor-Edwards, C.; Ridgway, W.; Dinisco, C.; Steinman, L.; Dalton, D.; Fathman, C.G. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol 1996, 156, 5–7. [Google Scholar]
- Heremans, H.; Dillen, C.; Groenen, M.; Martens, E.; Billiau, A. Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: Enhancement by monoclonal antibodies against interferon-γ. Eur. J. Immunol 1996, 26, 2393–2398. [Google Scholar]
- Chu, C.Q.; Wittmer, S.; Dalton, D.K. Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J. Exp. Med 2000, 192, 123–128. [Google Scholar]
- Becher, B.; Durell, B.G.; Noelle, R.J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest 2002, 110, 493–497. [Google Scholar]
- Gran, B.; Zhang, G.X.; Yu, S.; Li, J.; Chen, X.H.; Ventura, E.S.; Kamoun, M.; Rostami, A. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: Evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J. Immunol 2002, 169, 7104–7110. [Google Scholar]
- Cua, D.J.; Sherlock, J.; Chen, Y.; Murphy, C.A.; Joyce, B.; Seymour, B.; Lucian, L.; To, W.; Kwan, S.; Churakova, T.; et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421, 744–748. [Google Scholar]
- Langrish, C.L.; Chen, Y.; Blumenschein, W.M.; Mattson, J.; Basham, B.; Sedgwick, J.D.; McClanahan, T.; Kastelein, R.A.; Cua, D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med 2005, 201, 233–240. [Google Scholar]
- Mangan, P.R.; Harrington, L.E.; O’Quinn, D.B.; Helms, W.S.; Bullard, D.C.; Elson, C.O.; Hatton, R.D.; Wahl, S.M.; Schoeb, T.R.; Weaver, C.T. Transforming growth factor-β induces development of the T(H)17 lineage. Nature 2006, 441, 231–234. [Google Scholar]
- Harrington, L.E.; Hatton, R.D.; Mangan, P.R.; Turner, H.; Murphy, T.L.; Murphy, K.M.; Weaver, C.T. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol 2005, 6, 1123–1132. [Google Scholar]
- Durelli, L.; Conti, L.; Clerico, M.; Boselli, D.; Contessa, G.; Ripellino, P.; Ferrero, B.; Eid, P.; Novelli, F. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-β. Ann. Neurol 2009, 65, 499–509. [Google Scholar]
- Tzartos, J.S.; Friese, M.A.; Craner, M.J.; Palace, J.; Newcombe, J.; Esiri, M.M.; Fugger, L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol 2008, 172, 146–155. [Google Scholar]
- Kebir, H.; Kreymborg, K.; Ifergan, I.; Dodelet-Devillers, A.; Cayrol, R.; Bernard, M.; Giuliani, F.; Arbour, N.; Becher, B.; Prat, A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med 2007, 13, 1173–1175. [Google Scholar]
- Ransohoff, R.M. Immunology: In the beginning. Nature 2009, 462, 41–42. [Google Scholar]
- Tesmer, L.A.; Lundy, S.K.; Sarkar, S.; Fox, D.A. Th17 cells in human disease. Immunol. Rev 2008, 223, 87–113. [Google Scholar]
- Hofstetter, H.H.; Ibrahim, S.M.; Koczan, D.; Kruse, N.; Weishaupt, A.; Toyka, K.V.; Gold, R. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol 2005, 237, 123–130. [Google Scholar]
- Komiyama, Y.; Nakae, S.; Matsuki, T.; Nambu, A.; Ishigame, H.; Kakuta, S.; Sudo, K.; Iwakura, Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol 2006, 177, 566–573. [Google Scholar]
- Haak, S.; Croxford, A.L.; Kreymborg, K.; Heppner, F.L.; Pouly, S.; Becher, B.; Waisman, A. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest 2009, 119, 61–69. [Google Scholar]
- Nowak, E.C.; Weaver, C.T.; Turner, H.; Begum-Haque, S.; Becher, B.; Schreiner, B.; Coyle, A.J.; Kasper, L.H.; Noelle, R.J. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med 2009, 206, 1653–1660. [Google Scholar]
- Sutton, C.; Brereton, C.; Keogh, B.; Mills, K.H.; Lavelle, E.C. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J. Exp. Med 2006, 203, 1685–1691. [Google Scholar]
- Dardalhon, V.; Awasthi, A.; Kwon, H.; Galileos, G.; Gao, W.; Sobel, R.A.; Mitsdoerffer, M.; Strom, T.B.; Elyaman, W.; Ho, I.C.; et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat. Immunol 2008, 9, 1347–1355. [Google Scholar]
- Veldhoen, M.; Uyttenhove, C.; van Snick, J.; Helmby, H.; Westendorf, A.; Buer, J.; Martin, B.; Wilhelm, C.; Stockinger, B. Transforming growth factor-β ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol 2008, 9, 1341–1346. [Google Scholar]
- Soroosh, P.; Doherty, T.A. Th9 and allergic disease. Immunology 2009, 127, 450–458. [Google Scholar]
- Wucherpfennig, K.W.; Newcombe, J.; Li, H.; Keddy, C.; Cuzner, M.L.; Hafler, D.A. Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc. Natl. Acad. Sci. USA 1992, 89, 4588–4592. [Google Scholar]
- Shimonkevitz, R.; Colburn, C.; Burnham, J.A.; Murray, R.S.; Kotzin, B.L. Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis. Proc. Natl. Acad. Sci. USA 1993, 90, 923–927. [Google Scholar]
- Lockhart, E.; Green, A.M.; Flynn, J.L. IL-17 production is dominated by γδ T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J. Immunol 2006, 177, 4662–4669. [Google Scholar]
- Shibata, K.; Yamada, H.; Hara, H.; Kishihara, K.; Yoshikai, Y. Resident Vδ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J. Immunol 2007, 178, 4466–4472. [Google Scholar]
- Sutton, C.E.; Lalor, S.J.; Sweeney, C.M.; Brereton, C.F.; Lavelle, E.C.; Mills, K.H. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 2009, 31, 331–341. [Google Scholar]
- Kobayashi, Y.; Kawai, K.; Ito, K.; Honda, H.; Sobue, G.; Yoshikai, Y. Aggravation of murine experimental allergic encephalomyelitis by administration of T-cell receptor γδ-specific antibody. J. Neuroimmunol 1997, 73, 169–174. [Google Scholar]
- Ponomarev, E.D.; Dittel, B.N. γδ T cells regulate the extent and duration of inflammation in the central nervous system by a Fas ligand-dependent mechanism. J. Immunol 2005, 174, 4678–4687. [Google Scholar]
- Ponomarev, E.D.; Novikova, M.; Yassai, M.; Szczepanik, M.; Gorski, J.; Dittel, B.N. γδ T cell regulation of IFN-γ production by central nervous system-infiltrating encephalitogenic T cells: Correlation with recovery from experimental autoimmune encephalomyelitis. J. Immunol 2004, 173, 1587–1595. [Google Scholar]
- Rajan, A.J.; Gao, Y.L.; Raine, C.S.; Brosnan, C.F. A pathogenic role for gamma delta T cells in relapsing-remitting experimental allergic encephalomyelitis in the SJL mouse. J. Immunol 1996, 157, 941–949. [Google Scholar]
- Rajan, A.J.; Klein, J.D.; Brosnan, C.F. The effect of γδ T cell depletion on cytokine gene expression in experimental allergic encephalomyelitis. J. Immunol 1998, 160, 5955–5962. [Google Scholar]
- Spahn, T.W.; Issazadah, S.; Salvin, A.J.; Weiner, H.L. Decreased severity of myelin oligodendrocyte glycoprotein peptide 33–35-induced experimental autoimmune encephalomyelitis in mice with a disrupted TCR δ chain gene. Eur. J. Immunol 1999, 29, 4060–4071. [Google Scholar]
- Odyniec, A.; Szczepanik, M.; Mycko, M.P.; Stasiolek, M.; Raine, C.S.; Selmaj, K.W. γδ T cells enhance the expression of experimental autoimmune encephalomyelitis by promoting antigen presentation and IL-12 production. J. Immunol 2004, 173, 682–694. [Google Scholar]
- Cardona, A.E.; Teale, J.M. γ/δ T cell-deficient mice exhibit reduced disease severity and decreased inflammatory response in the brain in murine neurocysticercosis. J. Immunol 2002, 169, 3163–3171. [Google Scholar]
- Hori, S.; Sakaguchi, S. Foxp3: A critical regulator of the development and function of regulatory T cells. Microbes Infect 2004, 6, 745–751. [Google Scholar]
- Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol 2003, 4, 330–336. [Google Scholar]
- Sakaguchi, S.; Sakaguchi, N.; Asano, M.; Itoh, M.; Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol 1995, 155, 1151–1164. [Google Scholar]
- Roncarolo, M.G.; Gregori, S.; Battaglia, M.; Bacchetta, R.; Fleischhauer, K.; Levings, M.K. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev 2006, 212, 28–50. [Google Scholar]
- Martinez-Forero, I.; Garcia-Munoz, R.; Martinez-Pasamar, S.; Inoges, S.; Lopez-Diaz de Cerio, A.; Palacios, R.; Sepulcre, J.; Moreno, B.; Gonzalez, Z.; Fernandez-Diez, B.; et al. IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur. J. Immunol 2008, 38, 576–586. [Google Scholar]
- Astier, A.L.; Meiffren, G.; Freeman, S.; Hafler, D.A. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J. Clin. Invest 2006, 116, 3252–3257. [Google Scholar]
- Venken, K.; Hellings, N.; Thewissen, M.; Somers, V.; Hensen, K.; Rummens, J.L.; Medaer, R.; Hupperts, R.; Stinissen, P. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology 2008, 123, 79–89. [Google Scholar]
- Venken, K.; Hellings, N.; Hensen, K.; Rummens, J.L.; Medaer, R.; D’Hooghe, M.B.; Dubois, B.; Raus, J.; Stinissen, P. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J. Neurosci. Res 2006, 83, 1432–1446. [Google Scholar]
- Lafaille, J.J.; Nagashima, K.; Katsuki, M.; Tonegawa, S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 1994, 78, 399–408. [Google Scholar]
- Olivares-Villagomez, D.; Wang, Y.; Lafaille, J.J. Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J. Exp. Med 1998, 188, 1883–1894. [Google Scholar]
- Kohm, A.P.; Carpentier, P.A.; Anger, H.A.; Miller, S.D. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol 2002, 169, 4712–4716. [Google Scholar]
- Friese, M.A.; Fugger, L. Pathogenic CD8(+) T cells in multiple sclerosis. Ann. Neurol 2009, 66, 132–141. [Google Scholar]
- Weiss, H.A.; Millward, J.M.; Owens, T. CD8+ T cells in inflammatory demyelinating disease. J. Neuroimmunol 2007, 191, 79–85. [Google Scholar]
- Najafian, N.; Chitnis, T.; Salama, A.D.; Zhu, B.; Benou, C.; Yuan, X.; Clarkson, M.R.; Sayegh, M.H.; Khoury, S.J. Regulatory functions of CD8+CD28- T cells in an autoimmune disease model. J. Clin. Invest 2003, 112, 1037–1048. [Google Scholar]
- Lee, Y.H.; Ishida, Y.; Rifa’i, M.; Shi, Z.; Isobe, K.; Suzuki, H. Essential role of CD8+CD122+ regulatory T cells in the recovery from experimental autoimmune encephalomyelitis. J. Immunol 2008, 180, 825–832. [Google Scholar]
- Liu, Z.; Tugulea, S.; Cortesini, R.; Suciu-Foca, N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+CD28- T cells. Int. Immunol 1998, 10, 775–783. [Google Scholar]
- Ciubotariu, R.; Colovai, A.I.; Pennesi, G.; Liu, Z.; Smith, D.; Berlocco, P.; Cortesini, R.; Suciu-Foca, N. Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+CD28- regulatory T cells. J. Immunol 1998, 161, 5193–5202. [Google Scholar]
- Jiang, S.; Tugulea, S.; Pennesi, G.; Liu, Z.; Mulder, A.; Lederman, S.; Harris, P.; Cortesini, R.; Suciu-Foca, N. Induction of MHC-class I restricted human suppressor T cells by peptide priming in vitro. Hum. Immunol 1998, 59, 690–699. [Google Scholar]
- Li, J.; Liu, Z.; Jiang, S.; Cortesini, R.; Lederman, S.; Suciu-Foca, N. T suppressor lymphocytes inhibit NF-κB-mediated transcription of CD86 gene in APC. J. Immunol 1999, 163, 6386–6392. [Google Scholar]
- Colovai, A.I.; Liu, Z.; Ciubotariu, R.; Lederman, S.; Cortesini, R.; Suciu-Foca, N. Induction of xenoreactive CD4+ T-cell anergy by suppressor CD8+CD28- T cells. Transplantation 2000, 69, 1304–1310. [Google Scholar]
- Rifa’i, M.; Kawamoto, Y.; Nakashima, I.; Suzuki, H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J. Exp. Med 2004, 200, 1123–1134. [Google Scholar]
- Endharti, A.T.; Rifa, I.M.; Shi, Z.; Fukuoka, Y.; Nakahara, Y.; Kawamoto, Y.; Takeda, K.; Isobe, K.; Suzuki, H. Cutting edge: CD8+CD122+ regulatory T cells produce IL-10 to suppress IFN-γ production and proliferation of CD8+ T cells. J. Immunol 2005, 175, 7093–7097. [Google Scholar]
- Linker, R.A.; Rott, E.; Hofstetter, H.H.; Hanke, T.; Toyka, K.V.; Gold, R. EAE in beta-2 microglobulin-deficient mice: Axonal damage is not dependent on MHC-I restricted immune responses. Neurobiol. Dis 2005, 19, 218–228. [Google Scholar]
- Jiang, H.; Ware, R.; Stall, A.; Flaherty, L.; Chess, L.; Pernis, B. Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing Vβ8 TCR: A role of the Qa-1 molecule. Immunity 1995, 2, 185–194. [Google Scholar]
- Jiang, H.; Braunstein, N.S.; Yu, B.; Winchester, R.; Chess, L. CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice. Proc. Natl. Acad. Sci. USA 2001, 98, 6301–6306. [Google Scholar]
- Jiang, H.; Curran, S.; Ruiz-Vazquez, E.; Liang, B.; Winchester, R.; Chess, L. Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor Vβ repertoire during experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2003, 100, 8378–8383. [Google Scholar]
- Hu, D.; Ikizawa, K.; Lu, L.; Sanchirico, M.E.; Shinohara, M.L.; Cantor, H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat. Immunol 2004, 5, 516–523. [Google Scholar]
- Chen, M.L.; Yan, B.S.; Kozoriz, D.; Weiner, H.L. Novel CD8+ Treg suppress EAE by TGF-β- and IFN-γ-dependent mechanisms. Eur. J. Immunol 2009, 39, 3423–3435. [Google Scholar]
- Lucchinetti, C.; Bruck, W.; Parisi, J.; Scheithauer, B.; Rodriguez, M.; Lassmann, H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol 2000, 47, 707–717. [Google Scholar]
- Breij, E.C.; Brink, B.P.; Veerhuis, R.; van den Berg, C.; Vloet, R.; Yan, R.; Dijkstra, C.D.; van der Valk, P.; Bo, L. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann. Neurol 2008, 63, 16–25. [Google Scholar]
- Reindl, M.; Linington, C.; Brehm, U.; Egg, R.; Dilitz, E.; Deisenhammer, F.; Poewe, W.; Berger, T. Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: A comparative study. Brain 1999, 122, 2047–2056. [Google Scholar]
- Van der Goes, A.; Kortekaas, M.; Hoekstra, K.; Dijkstra, C.D.; Amor, S. The role of anti-myelin (auto)-antibodies in the phagocytosis of myelin by macrophages. J. Neuroimmunol 1999, 101, 61–67. [Google Scholar]
- Menon, K.K.; Piddlesden, S.J.; Bernard, C.C. Demyelinating antibodies to myelin oligodendrocyte glycoprotein and galactocerebroside induce degradation of myelin basic protein in isolated human myelin. J. Neurochem 1997, 69, 214–222. [Google Scholar]
- Link, H.; Baig, S.; Jiang, Y.P.; Olsson, O.; Hojeberg, B.; Kostulas, V.; Olsson, T. B cells and antibodies in MS. Res. Immunol 1989, 140, 219–226, Discussion 245–218. [Google Scholar]
- Lalive, P.H. Autoantibodies in inflammatory demyelinating diseases of the central nervous system. Swiss Med. Wkly 2008, 138, 692–707. [Google Scholar]
- Vyshkina, T.; Kalman, B. Autoantibodies and neurodegeneration in multiple sclerosis. Lab. Invest 2008, 88, 796–807. [Google Scholar]
- Hauser, S.L.; Waubant, E.; Arnold, D.L.; Vollmer, T.; Antel, J.; Fox, R.J.; Bar-Or, A.; Panzara, M.; Sarkar, N.; Agarwal, S.; et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med 2008, 358, 676–688. [Google Scholar]
- Harp, C.T.; Lovett-Racke, A.E.; Racke, M.K.; Frohman, E.M.; Monson, N.L. Impact of myelin-specific antigen presenting B cells on T cell activation in multiple sclerosis. Clin. Immunol 2008, 128, 382–391. [Google Scholar]
- Correale, J.; Farez, M. Helminth antigens modulate immune responses in cells from multiple sclerosis patients through TLR2-dependent mechanisms. J. Immunol 2009, 183, 5999–6012. [Google Scholar]
- Steinman, R.M.; Banchereau, J. Taking dendritic cells into medicine. Nature 2007, 449, 419–426. [Google Scholar]
- Zozulya, A.L.; Clarkson, B.D.; Ortler, S.; Fabry, Z.; Wiendl, H. The role of dendritic cells in CNS autoimmunity. J. Mol. Med. (Berl) 2010, 88, 535–544. [Google Scholar]
- Menges, M.; Rossner, S.; Voigtlander, C.; Schindler, H.; Kukutsch, N.A.; Bogdan, C.; Erb, K.; Schuler, G.; Lutz, M.B. Repetitive injections of dendritic cells matured with tumor necrosis factor α induce antigen-specific protection of mice from autoimmunity. J. Exp. Med 2002, 195, 15–21. [Google Scholar]
- Serafini, B.; Rosicarelli, B.; Magliozzi, R.; Stigliano, E.; Capello, E.; Mancardi, G.L.; Aloisi, F. Dendritic cells in multiple sclerosis lesions: Maturation stage, myelin uptake, and interaction with proliferating T cells. J. Neuropathol. Exp. Neurol 2006, 65, 124–141. [Google Scholar]
- Karni, A.; Abraham, M.; Monsonego, A.; Cai, G.; Freeman, G.J.; Hafler, D.; Khoury, S.J.; Weiner, H.L. Innate immunity in multiple sclerosis: Myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J. Immunol 2006, 177, 4196–4202. [Google Scholar]
- Fabriek, B.O.; van Haastert, E.S.; Galea, I.; Polfliet, M.M.; Dopp, E.D.; van Den Heuvel, M.M.; van Den Berg, T.K.; de Groot, C.J.; van Der Valk, P.; Dijkstra, C.D. CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 2005, 51, 297–305. [Google Scholar]
- Van Zwam, M.; Huizinga, R.; Melief, M.J.; Wierenga-Wolf, A.F.; van Meurs, M.; Voerman, J.S.; Biber, K.P.; Boddeke, H.W.; Hopken, U.E.; Meisel, C.; et al. Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE. J. Mol. Med. (Berl) 2009, 87, 273–286. [Google Scholar]
- Reubinoff, B.E.; Pera, M.F.; Fong, C.Y.; Trounson, A.; Bongso, A. Embryonic stem cell lines from human blastocysts: Somatic differentiation in vitro. Nat. Biotechnol 2000, 18, 399–404. [Google Scholar]
- Thomson, J.A.; Itskovitz-Eldor, J.; Shapiro, S.S.; Waknitz, M.A.; Swiergiel, J.J.; Marshall, V.S.; Jones, J.M. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282, 1145–1147. [Google Scholar]
- Kehat, I.; Kenyagin-Karsenti, D.; Snir, M.; Segev, H.; Amit, M.; Gepstein, A.; Livne, E.; Binah, O.; Itskovitz-Eldor, J.; Gepstein, L. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Invest 2001, 108, 407–414. [Google Scholar]
- Lavon, N.; Benvenisty, N. Differentiation and genetic manipulation of human embryonic stem cells and the analysis of the cardiovascular system. Trends Cardiovasc. Med 2003, 13, 47–52. [Google Scholar]
- Augello, A.; Kurth, T.B.; de Bari, C. Mesenchymal stem cells: A perspective from in vitro cultures to in vivo migration and niches. Eur. Cell Mater 2010, 20, 121–133. [Google Scholar]
- Krampera, M.; Pizzolo, G.; Aprili, G.; Franchini, M. Mesenchymal stem cells for bone, cartilage, tendon and skeletal muscle repair. Bone 2006, 39, 678–683. [Google Scholar]
- Li, C.; Zhang, W.; Jiang, X.; Mao, N. Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells. Cell Tissue Res 2007, 330, 437–446. [Google Scholar]
- Zhang, X.; Mitsuru, A.; Igura, K.; Takahashi, K.; Ichinose, S.; Yamaguchi, S.; Takahashi, T.A. Mesenchymal progenitor cells derived from chorionic villi of human placenta for cartilage tissue engineering. Biochem. Biophys. Res. Commun 2006, 340, 944–952. [Google Scholar]
- Chang, C.J.; Yen, M.L.; Chen, Y.C.; Chien, C.C.; Huang, H.I.; Bai, C.H.; Yen, B.L. Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-γ. Stem. Cells 2006, 24, 2466–2477. [Google Scholar]
- Jones, B.J.; Brooke, G.; Atkinson, K.; McTaggart, S.J. Immunosuppression by placental indoleamine 2,3-dioxygenase: A role for mesenchymal stem cells. Placenta 2007, 28, 1174–1181. [Google Scholar]
- Brooke, G.; Tong, H.; Levesque, J.P.; Atkinson, K. Molecular trafficking mechanisms of multipotent mesenchymal stem cells derived from human bone marrow and placenta. Stem. Cells Dev 2008, 17, 929–940. [Google Scholar]
- Lee, M.Y.; Huang, J.P.; Chen, Y.Y.; Aplin, J.D.; Wu, Y.H.; Chen, C.Y.; Chen, P.C.; Chen, C.P. Angiogenesis in differentiated placental multipotent mesenchymal stromal cells is dependent on integrin α5β1. PLoS One 2009, 4. [Google Scholar] [CrossRef]
- Chen, L.; He, D.M.; Zhang, Y. The differentiation of human placenta-derived mesenchymal stem cells into dopaminergic cells in vitro. Cell Mol. Biol. Lett 2009, 14, 528–536. [Google Scholar]
- Li, G.; Zhang, X.A.; Wang, H.; Wang, X.; Meng, C.L.; Chan, C.Y.; Yew, D.T.; Tsang, K.S.; Li, K.; Tsai, S.N.; et al. Comparative proteomic analysis of mesenchymal stem cells derived from human bone marrow, umbilical cord, and placenta: Implication in the migration. Proteomics 2009, 9, 20–30. [Google Scholar]
- Hiwase, S.D.; Dyson, P.G.; To, L.B.; Lewis, I.D. Cotransplantation of placental mesenchymal stromal cells enhances single and double cord blood engraftment in nonobese diabetic/severe combined immune deficient mice. Stem. Cells 2009, 27, 2293–2300. [Google Scholar]
- Semenov, O.V.; Koestenbauer, S.; Riegel, M.; Zech, N.; Zimmermann, R.; Zisch, A.H.; Malek, A. Multipotent mesenchymal stem cells from human placenta: Critical parameters for isolation and maintenance of stemness after isolation. Am. J. Obstet. Gynecol 2010, 202, 193.e1–193.e13. [Google Scholar]
- Portmann-Lanz, C.B.; Schoeberlein, A.; Huber, A.; Sager, R.; Malek, A.; Holzgreve, W.; Surbek, D.V. Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Am. J. Obstet. Gynecol 2006, 194, 664–673. [Google Scholar]
- Hwang, J.H.; Shim, S.S.; Seok, O.S.; Lee, H.Y.; Woo, S.K.; Kim, B.H.; Song, H.R.; Lee, J.K.; Park, Y.K. Comparison of cytokine expression in mesenchymal stem cells from human placenta, cord blood, and bone marrow. J. Korean Med. Sci 2009, 24, 547–554. [Google Scholar]
- Ilancheran, S.; Michalska, A.; Peh, G.; Wallace, E.M.; Pera, M.; Manuelpillai, U. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol. Reprod 2007, 77, 577–588. [Google Scholar]
- Deuse, T.; Stubbendorff, M.; Tang-Quan, K.; Phillips, N.; Kay, M.A.; Eiermann, T.; Phan, T.T.; Volk, H.D.; Reichenspurner, H.; Robbins, R.C.; et al. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 2011, 20, 655–667. [Google Scholar]
- In’t Anker, P.S.; Scherjon, S.A.; Kleijburg-van der Keur, C.; Noort, W.A.; Claas, F.H.; Willemze, R.; Fibbe, W.E.; Kanhai, H.H. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 2003, 102, 1548–1549. [Google Scholar]
- Tomic, S.; Djokic, J.; Vasilijic, S.; Vucevic, D.; Todorovic, V.; Supic, G.; Colic, M. Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by toll-like receptor agonists. Stem. Cells Dev 2011, 20, 695–708. [Google Scholar]
- Bartholomew, A.; Sturgeon, C.; Siatskas, M.; Ferrer, K.; McIntosh, K.; Patil, S.; Hardy, W.; Devine, S.; Ucker, D.; Deans, R.; et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol 2002, 30, 42–48. [Google Scholar]
- Djouad, F.; Bony, C.; Haupl, T.; Uze, G.; Lahlou, N.; Louis-Plence, P.; Apparailly, F.; Canovas, F.; Reme, T.; Sany, J.; et al. Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells. Arthritis Res. Ther 2005, 7, R1304–R1315. [Google Scholar]
- Tse, W.T.; Pendleton, J.D.; Beyer, W.M.; Egalka, M.C.; Guinan, E.C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: Implications in transplantation. Transplantation 2003, 75, 389–397. [Google Scholar]
- Bocelli-Tyndall, C.; Bracci, L.; Schaeren, S.; Feder-Mengus, C.; Barbero, A.; Tyndall, A.; Spagnoli, G.C. Human bone marrow mesenchymal stem cells and chondrocytes promote and/or suppress the in vitro proliferation of lymphocytes stimulated by interleukins 2, 7 and 15. Ann. Rheum. Dis 2009, 68, 1352–1359. [Google Scholar]
- Schurgers, E.; Kelchtermans, H.; Mitera, T.; Geboes, L.; Matthys, P. Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis. Arthritis Res. Ther 2010, 12. [Google Scholar] [CrossRef]
- Chen, C.P.; Liu, S.H.; Huang, J.P.; Aplin, J.D.; Wu, Y.H.; Chen, P.C.; Hu, C.S.; Ko, C.C.; Lee, M.Y.; Chen, C.Y. Engraftment potential of human placenta-derived mesenchymal stem cells after in utero transplantation in rats. Hum. Reprod 2009, 24, 154–165. [Google Scholar]
- Chang, Y.J.; Hwang, S.M.; Tseng, C.P.; Cheng, F.C.; Huang, S.H.; Hsu, L.F.; Hsu, L.W.; Tsai, M.S. Isolation of mesenchymal stem cells with neurogenic potential from the mesoderm of the amniotic membrane. Cells Tissues Organs 2010, 192, 93–105. [Google Scholar]
- Bailo, M.; Soncini, M.; Vertua, E.; Signoroni, P.B.; Sanzone, S.; Lombardi, G.; Arienti, D.; Calamani, F.; Zatti, D.; Paul, P.; et al. Engraftment potential of human amnion and chorion cells derived from term placenta. Transplantation 2004, 78, 1439–1448. [Google Scholar]
- Wolbank, S.; Peterbauer, A.; Fahrner, M.; Hennerbichler, S.; van Griensven, M.; Stadler, G.; Redl, H.; Gabriel, C. Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: A comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng 2007, 13, 1173–1183. [Google Scholar]
- Gotherstrom, C.; Ringden, O.; Westgren, M.; Tammik, C.; Le Blanc, K. Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells. Bone Marrow Transplant 2003, 32, 265–272. [Google Scholar]
- Giuliani, M.; Fleury, M.; Vernochet, A.; Ketroussi, F.; Clay, D.; Azzarone, B.; Lataillade, J.J.; Durrbach, A. Long-lasting inhibitory effects of fetal liver mesenchymal stem cells on T-lymphocyte proliferation. PLoS One 2011, 6. [Google Scholar] [CrossRef]
- Zheng, Z.H.; Li, X.Y.; Ding, J.; Jia, J.F.; Zhu, P. Allogeneic mesenchymal stem cell and mesenchymal stem cell-differentiated chondrocyte suppress the responses of type II collagen-reactive T cells in rheumatoid arthritis. Rheumatology (Oxford) 2008, 47, 22–30. [Google Scholar]
- Petrini, I.; Pacini, S.; Petrini, M.; Fazzi, R.; Trombi, L.; Galimberti, S. Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma-delta T cells. Eur. J. Clin. Invest 2009, 39, 813–818. [Google Scholar]
- Augello, A.; Tasso, R.; Negrini, S.M.; Amateis, A.; Indiveri, F.; Cancedda, R.; Pennesi, G. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur. Immunol 2005, 35, 1482–1490. [Google Scholar]
- Xue, Q.; Luan, X.Y.; Gu, Y.Z.; Wu, H.Y.; Zhang, G.B.; Yu, G.H.; Zhu, H.T.; Wang, M.; Dong, W.; Geng, Y.J.; et al. The negative co-signaling molecule b7-h4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem. Cells Dev 2010, 19, 27–38. [Google Scholar]
- Glennie, S.; Soeiro, I.; Dyson, P.J.; Lam, E.W.; Dazzi, F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005, 105, 2821–2827. [Google Scholar]
- Corcione, A.; Benvenuto, F.; Ferretti, E.; Giunti, D.; Cappiello, V.; Cazzanti, F.; Risso, M.; Gualandi, F.; Mancardi, G.L.; Pistoia, V.; et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006, 107, 367–372. [Google Scholar]
- Asari, S.; Itakura, S.; Ferreri, K.; Liu, C.P.; Kuroda, Y.; Kandeel, F.; Mullen, Y. Mesenchymal stem cells suppress B-cell terminal differentiation. Exp. Hematol 2009, 37, 604–615. [Google Scholar]
- Angoulvant, D.; Clerc, A.; Benchalal, S.; Galambrun, C.; Farre, A.; Bertrand, Y.; Eljaafari, A. Human mesenchymal stem cells suppress induction of cytotoxic response to alloantigens. Biorheology 2004, 41, 469–476. [Google Scholar]
- Rasmusson, I.; Ringden, O.; Sundberg, B.; Le Blanc, K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003, 76, 1208–1213. [Google Scholar]
- Spaggiari, G.M.; Capobianco, A.; Becchetti, S.; Mingari, M.C.; Moretta, L. Mesenchymal stem cell-natural killer cell interactions: Evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 2006, 107, 1484–1490. [Google Scholar]
- Poggi, A.; Prevosto, C.; Massaro, A.M.; Negrini, S.; Urbani, S.; Pierri, I.; Saccardi, R.; Gobbi, M.; Zocchi, M.R. Interaction between human NK cells and bone marrow stromal cells inducesNK cell triggering: Role of NKp30 and NKG2D receptors. J. Immunol 2005, 175, 6352–6360. [Google Scholar]
- Hoogduijn, M.J.; Korevaar, S.S.; Engela, A.U.; Weimar, W.; Baan, C.C. Immunological aspects of allogeneic and autologous mesenchymal stem cell therapies. Hum. Gene Ther 2011, 22, 1587–1591. [Google Scholar]
- Crop, M.J.; Korevaar, S.S.; de Kuiper, R.; Ijzermans, J.N.; van Besouw, N.M.; Baan, C.C.; Weimar, W.; Hoogduijn, M.J. Human mesenchymal stem cells are susceptible to lysis by CD8+ T-cells and NK cells. Cell Transplant 2011. [Google Scholar] [CrossRef]
- Gonzalez, M.A.; Gonzalez-Rey, E.; Rico, L.; Buscher, D.; Delgado, M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 2009, 136, 978–989. [Google Scholar]
- Christensen, M.E.; Turner, B.E.; Sinfield, L.J.; Kollar, K.; Cullup, H.; Waterhouse, N.J.; Hart, D.N.; Atkinson, K.; Rice, A.M. Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease. Haematologica 2010, 95, 2102–2110. [Google Scholar]
- Aggarwal, S.; Pittenger, M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005, 105, 1815–1822. [Google Scholar]
- Groh, M.E.; Maitra, B.; Szekely, E.; Koc, O.N. Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp. Hematol 2005, 33, 928–934. [Google Scholar]
- Djouad, F.; Plence, P.; Bony, C.; Tropel, P.; Apparailly, F.; Sany, J.; Noel, D.; Jorgensen, C. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003, 102, 3837–3844. [Google Scholar]
- Abumaree, M.; Al Jumah, M.; Pace, R.A.; Kalionis, B. Immunosuppressive properties of mesenchymal stem cells. Stem. Cell Rev 2012, 8, 375–392. [Google Scholar]
- Jiang, X.X.; Zhang, Y.; Liu, B.; Zhang, S.X.; Wu, Y.; Yu, X.D.; Mao, N. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005, 105, 4120–4126. [Google Scholar]
- Zhang, Y.; Li, C.; Jiang, X.; Zhang, S.; Wu, Y.; Liu, B.; Tang, P.; Mao, N. Human placenta-derived mesenchymal progenitor cells support culture expansion of long-term culture-initiating cells from cord blood CD34+ cells. Exp. Hematol 2004, 32, 657–664. [Google Scholar]
- Xu, G.; Zhang, L.; Ren, G.; Yuan, Z.; Zhang, Y.; Zhao, R.C.; Shi, Y. Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res 2007, 17, 240–248. [Google Scholar]
- Bian, L.; Guo, Z.K.; Wang, H.X.; Wang, J.S.; Wang, H.; Li, Q.F.; Yang, Y.F.; Xiao, F.J.; Wu, C.T.; Wang, L.S. In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells. In Vivo 2009, 23, 21–27. [Google Scholar]
- Cargnoni, A.; Gibelli, L.; Tosini, A.; Signoroni, P.B.; Nassuato, C.; Arienti, D.; Lombardi, G.; Albertini, A.; Wengler, G.S.; Parolini, O. Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant 2009, 18, 405–422. [Google Scholar]
- Devine, S.M.; Bartholomew, A.M.; Mahmud, N.; Nelson, M.; Patil, S.; Hardy, W.; Sturgeon, C.; Hewett, T.; Chung, T.; Stock, W.; et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp. Hematol 2001, 29, 244–255. [Google Scholar]
- Lu, X.; Liu, T.; Gu, L.; Huang, C.; Zhu, H.; Meng, W.; Xi, Y.; Li, S.; Liu, Y. Immunomodulatory effects of mesenchymal stem cells involved in favoring type 2 T cell subsets. Transpl. Immunol 2009, 22, 55–61. [Google Scholar]
- Kopen, G.C.; Prockop, D.J.; Phinney, D.G. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc. Natl. Acad. Sci USA 1999, 96, 10711–10716. [Google Scholar]
- Devine, S.M.; Cobbs, C.; Jennings, M.; Bartholomew, A.; Hoffman, R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003, 101, 2999–3001. [Google Scholar]
- Sanchez-Ramos, J.; Song, S.; Cardozo-Pelaez, F.; Hazzi, C.; Stedeford, T.; Willing, A.; Freeman, T.B.; Saporta, S.; Janssen, W.; Patel, N.; et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol 2000, 164, 247–256. [Google Scholar]
- Woodbury, D.; Schwarz, E.J.; Prockop, D.J.; Black, I.B. Adult rat and human bone marrow stromal cells differentiate into neurons. J. Neurosci. Res 2000, 61, 364–370. [Google Scholar]
- Woodbury, D.; Reynolds, K.; Black, I.B. Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J. Neurosci. Res 2002, 69, 908–917. [Google Scholar]
- Azizi, S.A.; Stokes, D.; Augelli, B.J.; DiGirolamo, C.; Prockop, D.J. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats—similarities to astrocyte grafts. Proc. Natl. Acad. Sci. USA 1998, 95, 3908–3913. [Google Scholar]
- Chen, J.; Li, Y.; Wang, L.; Lu, M.; Zhang, X.; Chopp, M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J. Neurol. Sci 2001, 189, 49–57. [Google Scholar]
- Zhang, J.; Li, Y.; Chen, J.; Yang, M.; Katakowski, M.; Lu, M.; Chopp, M. Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res 2004, 1030, 19–27. [Google Scholar]
- Zhao, L.R.; Duan, W.M.; Reyes, M.; Keene, C.D.; Verfaillie, C.M.; Low, W.C. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp. Neurol 2002, 174, 11–20. [Google Scholar]
- Munoz-Elias, G.; Marcus, A.J.; Coyne, T.M.; Woodbury, D.; Black, I.B. Adult bone marrow stromal cells in the embryonic brain: Engraftment, migration, differentiation, and long-term survival. J. Neurosci 2004, 24, 4585–4595. [Google Scholar]
- Lepski, G.; Jannes, C.E.; Strauss, B.; Marie, S.K.; Nikkhah, G. Survival and neuronal differentiation of mesenchymal stem cells transplanted into the rodent brain are dependent upon microenvironment. Tissue Eng. Part A 2010, 16, 2769–2782. [Google Scholar]
- Park, S.; Kim, E.; Koh, S.E.; Maeng, S.; Lee, W.D.; Lim, J.; Shim, I.; Lee, Y.J. Dopaminergic differentiation of neural progenitors derived from placental mesenchymal stem cells in the brains of Parkinson’s disease model rats and alleviation of asymmetric rotational behavior. Brain Res 2012, 1466, 158–166. [Google Scholar]
- Zhang, J.; Li, Y.; Chen, J.; Cui, Y.; Lu, M.; Elias, S.B.; Mitchell, J.B.; Hammill, L.; Vanguri, P.; Chopp, M. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp. Neurol 2005, 195, 16–26. [Google Scholar]
- Zhang, J.; Li, Y.; Lu, M.; Cui, Y.; Chen, J.; Noffsinger, L.; Elias, S.B.; Chopp, M. Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice. J. Neurosci. Res 2006, 84, 587–595. [Google Scholar]
- Liu, X.J.; Zhang, J.F.; Sun, B.; Peng, H.S.; Kong, Q.F.; Bai, S.S.; Liu, Y.M.; Wang, G.Y.; Wang, J.H.; Li, H.L. Reciprocal effect of mesenchymal stem cell on experimental autoimmune encephalomyelitis is mediated by transforming growth factor-beta and interleukin-6. Clin. Exp. Immunol 2009, 158, 37–44. [Google Scholar]
- Peron, J.P.; Jazedje, T.; Brandao, W.N.; Perin, P.M.; Maluf, M.; Evangelista, L.P.; Halpern, S.; Nisenbaum, M.G.; Czeresnia, C.E.; Zatz, M.; et al. Human endometrial-derived mesenchymal stem cells suppress inflammation in the central nervous system of EAE mice. Stem. Cell Rev 2011. [Google Scholar] [CrossRef]
- Barhum, Y.; Gai-Castro, S.; Bahat-Stromza, M.; Barzilay, R.; Melamed, E.; Offen, D. Intracerebroventricular transplantation of human mesenchymal stem cells induced to secrete neurotrophic factors attenuates clinical symptoms in a mouse model of multiple sclerosis. J. Mol. Neurosci 2010, 41, 129–137. [Google Scholar]
- Gordon, D.; Pavlovska, G.; Uney, J.B.; Wraith, D.C.; Scolding, N.J. Human mesenchymal stem cells infiltrate the spinal cord, reduce demyelination, and localize to white matter lesions in experimental autoimmune encephalomyelitis. J. Neuropathol. Exp. Neurol 2010, 69, 1087–1095. [Google Scholar]
- Fisher-Shoval, Y.; Barhum, Y.; Sadan, O.; Yust-Katz, S.; Ben-Zur, T.; Lev, N.; Benkler, C.; Hod, M.; Melamed, E.; Offen, D. Transplantation of placenta-derived mesenchymal stem cells in the EAE mouse model of MS. J. Mol. Neurosci 2012. [Google Scholar] [CrossRef]
- Bai, L.; Lennon, D.P.; Caplan, A.I.; Dechant, A.; Hecker, J.; Kranso, J.; Zaremba, A.; Miller, R.H. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat. Neurosci 2012. [Google Scholar] [CrossRef]
- Neuhuber, B.; Timothy Himes, B.; Shumsky, J.S.; Gallo, G.; Fischer, I. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 2005, 1035, 73–85. [Google Scholar]
- Rivera, F.J.; Couillard-Despres, S.; Pedre, X.; Ploetz, S.; Caioni, M.; Lois, C.; Bogdahn, U.; Aigner, L. Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells. Stem. Cells 2006, 24, 2209–2219. [Google Scholar]
- Rivera, F.J.; Siebzehnrubl, F.A.; Kandasamy, M.; Couillard-Despres, S.; Caioni, M.; Poehler, A.M.; Berninger, B.; Sandner, B.; Bogdahn, U.; Goetz, M.; et al. Mesenchymal stem cells promote oligodendroglial differentiation in hippocampal slice cultures. Cell Physiol. Biochem 2009, 24, 317–324. [Google Scholar]
- Phinney, D.G.; Prockop, D.J. Concise review: Mesenchymal stem/multipotent stromal cells: The state of transdifferentiation and modes of tissue repair–current views. Stem. Cells 2007, 25, 2896–2902. [Google Scholar]
- Mendez-Ferrer, S.; Michurina, T.V.; Ferraro, F.; Mazloom, A.R.; Macarthur, B.D.; Lira, S.A.; Scadden, D.T.; Ma’ayan, A.; Enikolopov, G.N.; Frenette, P.S. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010, 466, 829–834. [Google Scholar]
- Lee, R.H.; Pulin, A.A.; Seo, M.J.; Kota, D.J.; Ylostalo, J.; Larson, B.L.; Semprun-Prieto, L.; Delafontaine, P.; Prockop, D.J. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009, 5, 54–63. [Google Scholar]
- Parekkadan, B.; van Poll, D.; Suganuma, K.; Carter, E.A.; Berthiaume, F.; Tilles, A.W.; Yarmush, M.L. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One 2007, 2. [Google Scholar] [CrossRef]
- Scuteri, A.; Cassetti, A.; Tredici, G. Adult mesenchymal stem cells rescue dorsal root ganglia neurons from dying. Brain Res 2006, 1116, 75–81. [Google Scholar]
- Crigler, L.; Robey, R.C.; Asawachaicharn, A.; Gaupp, D.; Phinney, D.G. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp. Neurol 2006, 198, 54–64. [Google Scholar]
- Wilkins, A.; Kemp, K.; Ginty, M.; Hares, K.; Mallam, E.; Scolding, N. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009, 3, 63–70. [Google Scholar]
- Bai, L.; Caplan, A.; Lennon, D.; Miller, R.H. Human mesenchymal stem cells signals regulate neural stem cell fate. Neurochem. Res 2007, 32, 353–362. [Google Scholar]
- Akiyama, Y.; Radtke, C.; Honmou, O.; Kocsis, J.D. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002, 39, 229–236. [Google Scholar]
- Satake, K.; Lou, J.; Lenke, L.G. Migration of mesenchymal stem cells through cerebrospinal fluid into injured spinal cord tissue. Spine (Phila Pa 1976) 2004, 29, 1971–1979. [Google Scholar]
- Vercelli, A.; Mereuta, O.M.; Garbossa, D.; Muraca, G.; Mareschi, K.; Rustichelli, D.; Ferrero, I.; Mazzini, L.; Madon, E.; Fagioli, F. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis 2008, 31, 395–405. [Google Scholar]
- Chen, J.; Li, Y.; Katakowski, M.; Chen, X.; Wang, L.; Lu, D.; Lu, M.; Gautam, S.C.; Chopp, M. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J. Neurosci. Res 2003, 73, 778–786. [Google Scholar]
- Li, Y.; Chen, J.; Chen, X.G.; Wang, L.; Gautam, S.C.; Xu, Y.X.; Katakowski, M.; Zhang, L.J.; Lu, M.; Janakiraman, N.; et al. Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery. Neurology 2002, 59, 514–523. [Google Scholar]
- Munoz, J.R.; Stoutenger, B.R.; Robinson, A.P.; Spees, J.L.; Prockop, D.J. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc. Natl. Acad. Sci. USA 2005, 102, 18171–18176. [Google Scholar]
- Ohtaki, H.; Ylostalo, J.H.; Foraker, J.E.; Robinson, A.P.; Reger, R.L.; Shioda, S.; Prockop, D.J. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses. Proc. Natl. Acad. Sci. USA 2008, 105, 14638–14643. [Google Scholar]
- Zhou, C.; Zhang, C.; Chi, S.; Xu, Y.; Teng, J.; Wang, H.; Song, Y.; Zhao, R. Effects of human marrow stromal cells on activation of microglial cells and production of inflammatory factors induced by lipopolysaccharide. Brain Res 2009, 1269, 23–30. [Google Scholar]
- Kim, Y.J.; Park, H.J.; Lee, G.; Bang, O.Y.; Ahn, Y.H.; Joe, E.; Kim, H.O.; Lee, P.H. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia 2009, 57, 13–23. [Google Scholar]
- Lanza, C.; Morando, S.; Voci, A.; Canesi, L.; Principato, M.C.; Serpero, L.D.; Mancardi, G.; Uccelli, A.; Vergani, L. Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. J. Neurochem 2009, 110, 1674–1684. [Google Scholar]
- Bork, S.; Pfister, S.; Witt, H.; Horn, P.; Korn, B.; Ho, A.D.; Wagner, W. DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell 2010, 9, 54–63. [Google Scholar]
- Bonab, M.M.; Alimoghaddam, K.; Talebian, F.; Ghaffari, S.H.; Ghavamzadeh, A.; Nikbin, B. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006, 7. [Google Scholar] [CrossRef]
- Kassem, M.; Marie, P.J. Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell 2011, 10, 191–197. [Google Scholar]
- Mareschi, K.; Ferrero, I.; Rustichelli, D.; Aschero, S.; Gammaitoni, L.; Aglietta, M.; Madon, E.; Fagioli, F. Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J. Cell Biochem 2006, 97, 744–754. [Google Scholar]
- Moerman, E.J.; Teng, K.; Lipschitz, D.A.; Lecka-Czernik, B. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: The role of PPAR-γ2 transcription factor and TGF-β/BMP signaling pathways. Aging Cell 2004, 3, 379–389. [Google Scholar]
- Schallmoser, K.; Bartmann, C.; Rohde, E.; Bork, S.; Guelly, C.; Obenauf, A.C.; Reinisch, A.; Horn, P.; Ho, A.D.; Strunk, D.; et al. Replicative senescence-associated gene expression changes in mesenchymal stromal cells are similar under different culture conditions. Haematologica 2010, 95, 867–874. [Google Scholar]
- Stolzing, A.; Scutt, A. Age-related impairment of mesenchymal progenitor cell function. Aging Cell 2006, 5, 213–224. [Google Scholar]
- Tokalov, S.V.; Gruener, S.; Schindler, S.; Iagunov, A.S.; Baumann, M.; Abolmaali, N.D. A number of bone marrow mesenchymal stem cells but neither phenotype nor differentiation capacities changes with age of rats. Mol. Cells 2007, 24, 255–260. [Google Scholar]
- Wagner, W.; Ho, A.D.; Zenke, M. Different facets of aging in human mesenchymal stem cells. Tissue Eng. Part B Rev 2010, 16, 445–453. [Google Scholar]
- Wilson, A.; Shehadeh, L.A.; Yu, H.; Webster, K.A. Age-related molecular genetic changes of murine bone marrow mesenchymal stem cells. BMC Genomics 2010, 11. [Google Scholar] [CrossRef]
- Zhou, S.; Greenberger, J.S.; Epperly, M.W.; Goff, J.P.; Adler, C.; Leboff, M.S.; Glowacki, J. Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 2008, 7, 335–343. [Google Scholar]
- Bergman, R.J.; Gazit, D.; Kahn, A.J.; Gruber, H.; McDougall, S.; Hahn, T.J. Age-related changes in osteogenic stem cells in mice. J. Bone Miner. Res 1996, 11, 568–577. [Google Scholar]
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