Targeting Dendritic Cell Function during Systemic Autoimmunity to Restore Tolerance
Abstract
:1. Introduction
2. Targeting DC-T Cell Interactions to Prevent Autoimmunity
3. Targeting DC-B Cell Interactions to Prevent Autoimmunity
4. DC Abnormalities in Human Autoimmune Diseases
5. DC Maturation Stimuli during Autoimmunity
6. Designing New Therapies Based on Tolerogenic DCs
6.1. Metabolic Control
Agent | Protocol | Type of Tolerogenic Response | Targeted Disease | Reference | |||||
---|---|---|---|---|---|---|---|---|---|
Species | Differentiation | Relevant Antigen | Type of Study | ||||||
Dexamethasone and Vitamin D3 | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | alloantigen | in vitro; pre-clinical | Maturation-resistant phenotype, IL10/IL12; Impact in metabolism (lipids, glucose and oxidative phosphorylation); Migratory phenotype alterations; Reduce T cell priming and allospecific T cell response | Immune-mediated diseases; Prevention of graft rejection; Rheumatoid arthitis; Sjogren syndrome | Ferreira
et al., 2011 [141]; Volchenkov et al., 2013 [148]; Volchenkov et al., 2013 [150]; Xing et al., 2002 [151]; Unger et al., 2009 [152]; García-González et al., 2013 [153] | ||
mouse | Bone marrow, GM-CSF, 5 days | - | in vivo | T cell priming; Maturation-resistant phenotype, IL10/IL12; Reduction of proinflammatory chemokines and cytokines | Immune-mediated diseases | Xing et al., 2002 [151] | |||
mouse | Bone marrow, GM-CSF, 5 days | - | in vitro | T cell priming; Maturation-resistant phenotype, IL10/IL12 | Immune-mediated diseases | Moser et al., 1995 [154] | |||
Dexamethasone plus monophosphoryl lipid A | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | alloantigen | in vitro; pre-clinical | Stable phenotype and migratory capacity to lymphoid chemokines; T cell priming; Maturation-resistant phenotype, IL10/IL12 | Rheumatoid arthitis; Immune-mediated diseases; Prevention of graft rejection | García-González et al., 2013 [153] | ||
Dexamethasone | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | - | in vitro | Maturation-resistant phenotype, IL10/IL12; T cell priming | Immune-mediated diseases | Rea et al., 2000 [155] | ||
Vitamin D3 | mouse | Bone marrow, GM-CSF, 5 days | - | in vivo | Reduce EAE severity; Maturation-resistant phenotype, IL10/IL12; Regulatory T cell induction | EAE; Autoimmunity | Farías et al., 2013 [156]; Unger et al., 2009 [152] | ||
human | Blood monocytes, GM-CSF and IL-4, 5–6 days | myelin peptides | in vitro | Maturation-resistant phenotype, IL10/IL12; Reduce autoreactive T cell induction | MS; Autoimmunity | Raïch-Regué et al., 2012 [157] | |||
Rapamycin | mouse | Bone marrow, GM-CSF, 5 days | alloantigen | in vitro | Maturation-resistant phenotype; Reduce T cell priming and allospecific T cell response | prevention of graft rejection | Turnquist et al., 2007 [143]; Taner et al., 2005 [144]; Hackstein et al., 2003 [158] | ||
mouse | Bone marrow, GM-CSF, 5 days | alloantigen | in vivo | Reduce survival of alloantigen-specific CD8+ T cells in vivo | Prevention of graft rejection | Fischer et al., 2011 [145] | |||
human | Blood monocytes, GM-CSF and IL-4, 5–6 days | alloantigen | in vitro | Maturation-resistant phenotype; Reduce T cell priming and allospecific T cell response | Immune-mediated diseases | Fedoric et al., 2008 [159] | |||
Andrographolide | mouse | Bone marrow, GM-CSF, 5 days | MOG peptide | in vitro | Reduce T cell priming and antigen processing; NF-κB inhibition | Autoimmunity; EAE | Iruretagoyena et al., 2005 [146] | ||
mouse | Bone marrow, GM-CSF, 5 days | MOG peptide | in vivo | Reduce EAE severity; NF-κB inhibition | Autoimmunity; EAE | Iruretagoyena et al., 2006 [149] | |||
Aspirin | mouse | Bone marrow, GM-CSF, 5 days | alloantigen | in vitro | Maturation-resistant phenotype; IL10/IL12; Phagocytosis inhibition; Reduce T cell primi | Immune-mediated diseases | Hackstein et al., 2001 [160]; Buckland et al., 2006 [161]; Cai et al., 2011 [162] | ||
Rosiglitazone | mouse | Bone marrow, GM-CSF, 5 days | MOG peptide | in vivo | Reduce T cell priming; Reduce EAE severity, NF-κB inhibition | Autoimmunity; EAE | Iruretagoyena et al., 2006 [149] | ||
human | Blood monocytes, GM-CSF and IL-4, 5–6 days | - | in vitro | Reduce proinflammatory cytokine expression; Lipid accumulation appears to be diminished in these cells | Immune-mediated diseases | Szatmari et al., 2007 [147] | |||
Troglitazone | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | - | in vitro | Maturation-resistant phenotype, IL10/IL12 | Immune-mediated diseases | Volchenkov et al., 2013 [148] | ||
Cobalt Protoporphyrin | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | alloantigen | in vitro | Reduce T cell priming; Maturation-resistant phenotype, IL10/IL12; Reduce allospecific T cell response | Immune-mediated diseases; Prevention of graft rejection | Chauveau et al., 2005 [163] | ||
Bay 11-7082 | mouse | Bone marrow, GM-CSF and IL-4, 5 days | methylated serum albumin | in vivo | Reduce disease severity; Reduce T cell response; NF-κB inhibition | CIA (Rheumatoid arthitis) | Martin et al., 2007 [164] | ||
mouse | Bone marrow, GM-CSF, 5 days | - | in vitro | Maturation-resistant phenotype, IL10/IL12 | Immune-mediated diseases | Ade et al., 2007 [165] | |||
Tacrolimus | mouse | Bone marrow, GM-CSF, 5 days | - | in vivo | - | CIA (Rheumatoid arthitis) | Ren et al., 2014 [166] | ||
human | Blood monocytes, GM-CSF and IL-4, 5–6 days | - | in vitro | Maturation-resistant phenotype, IL10/IL12; Anti-inflammatory cytokine gene expression | Rheumatoid arthitis | Ren et al., 2014 [166] | |||
IL-10 | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | alloantigen; allergen | in vitro; pre-clinical | Maturation-resistant phenotype, IL10/IL12; Reduce T cell priming and allospecific T cell response | Systemic Lupus Erythematosus; Type 1 Diabetes; Immune-mediated diseases; Asthma and allergy | Sato et al., 1999 [167]; Knodler et al., 2008 [168]; Velten et al., 2004 [169]; Kubsch et al., 2003 [170]; Steinbrink et al., 2002 [171]; Li et al., 2010 [172]; Lopez et al., 2011 [173]; Crispin et al., 2012 [28] | ||
mouse | Bone marrow, GM-CSF, 5 days | - | in vitro | Maturation-resistant phenotype | Immune-mediated diseases | Ruffner et al., 2009 [174] | |||
rat | Bone marrow, GM-CSF, 5 days | - | in vivo | Maturation-resistant phenotype; Reduce T cell priming and allospecific T cell response | Prevention of graft rejection | Jiang et al., 2004 [175] | |||
TGF-β | mouse | Bone marrow, GM-CSF, 5 days | insulin; allopeptides | in vivo | Long-term survival of the graft; Immune tolerance restoration | Prevention of graft rejection | Thomas et al., 2013 [176]; Yan et al, 2014 [177] | ||
IL-10 and TGF-β | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | insulin and GAD65; β2-glycoprotein I | in vitro; pre-clinical | Maturation-resistant phenotype, IL10/IL12; Reduced antigen specific T cell response | Antiphospholipid syndrome; Type 1 Diabetes | Segovia-Gamboa et al., 2014 [178]; Torres-Aguilar et al., 2012 [179] | ||
Cholera toxin B | human | Blood monocytes, GM-CSF and IL-4, 5–6 days | - | in vitro | Maturation-resistant phenotype; Reduce T cell priming; regulatory T cell induction | Immune-mediated diseases | D’ambrosio et al., 2008 [180] | ||
Gene therapy, IL-10 plus TGF-β | rat | Bone marrow, GM-CSF, 5 days | - | in vivo | Long-term survival of the graft; Maturation-resistant phenotype | Prevention of graft rejection | Chen et al., 2014 [181] | ||
Gene therapy; silencing; IL-12/IL23/CD40/CD80/CD86/RelB | mouse | Bone marrow, GM-CSF or GM-CSF and IL-4, 5 days | collagen II; MOG petide; islet lysate | in vivo | Reduce disease severity and joint erosion; Reduce T cell priming; Reduced islet-specific T cell response; Reduce severity of Type 1 Diabetes | CIA (Rheumatoid arthitis); EAE; Type 1 Diabetes | Li et al., 2012 [182]; Zheng et al., 2010 [183]; Kalantari et al., 2014 [184]; Ma et al., 2003 [185]; Machen et al., 2004 [186] |
6.2. Pharmacologic Intervention
Protocol for DC | Name | Targeted Disease | Results/Status | ClinicalTrials.gov Identifier | ||||
---|---|---|---|---|---|---|---|---|
Agent | Origin | Differentiation | Type of Study | Route | ||||
Dexamethasone and Vitamin D3 | Blood monocytes | GM-CSF and IL-4, 5–6 days | Phase I; Proof of safety | Arthroscopically | AutoDECRA | Rheumatoid arthitis | No study results posted; Ongoing study | NCT01352858 |
BAY11-7082 | Blood monocytes | GM-CSF and IL-4, 5–6 days | Phase I; Proof of safety | Intradermally | - | Rheumatoid arthitis (citrunillated peptides) | Safe and well tolerated; Ongoing study | - |
Gene therapy; siRNA; CD40/CD80/CDD86 | Blood monocytes | GM-CSF and IL-4, 5–6 days | Phase I; Proof of safety | Intradermally | - | Type 1 Diabetes | Safe and well tolerated; Ongoing study | NCT00445913 |
Low GM-CSF | Blood monocytes | low GM-CSF, 6 days | Phase I; feasibility study | Intravenous | The One Study | Kidney transplant | No study results posted; Ongoing study | - |
6.3. Biological Compounds
6.4. Gene Therapy
7. Conclusions
Acknowledgments
Abbreviations
APCs | Antigen presenting cells |
ANA | Anti-nuclear antibodies |
BAFF | B cell activating factor |
BLyS | B lymphocyte stimulator |
cDCs | Conventional dendritic cells |
CIA | Collagen induced arthritis |
CoPP | Cobalt Protoporphyrin |
DAMPs | Danger-associated molecular patterns |
DCs | Dendritic cells |
Dex | Dexamethasone |
EAE | Experimental Autoimmune Encephalitis |
HO-1 | Hemeoxygenase 1 |
IC | Immune complex |
ILT | Immunoglobulin-like Transcript |
MS | Multiple sclerosis |
mTOR | Mammalian target of rapamycin |
NF-κB | Nuclear factor kappa B |
PAMPs | Pathogen-associated molecular patterns |
PD-1 | Programmed death 1 |
pDCs | Plasmacytoid dendritic cells |
PPAR | Peroxysome proliferator-activated receptor |
RA | Rheumatoid Arthritis |
RAPA | Rapamycin |
RNAi | interference RNA |
SLE | Systemic Lupus Erythematosus |
SS | Sjögren’ |
s syndrome; T1D | Type 1 Diabetes |
Th | T helper |
TLRs | Toll Like Receptors |
Treg | Regulatory T cells |
VD3 | 1α,25-dihydroxyvitamin D3 |
Conflicts of Interest
References
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Mackern-Oberti, J.P.; Vega, F.; Llanos, C.; Bueno, S.M.; Kalergis, A.M. Targeting Dendritic Cell Function during Systemic Autoimmunity to Restore Tolerance. Int. J. Mol. Sci. 2014, 15, 16381-16417. https://doi.org/10.3390/ijms150916381
Mackern-Oberti JP, Vega F, Llanos C, Bueno SM, Kalergis AM. Targeting Dendritic Cell Function during Systemic Autoimmunity to Restore Tolerance. International Journal of Molecular Sciences. 2014; 15(9):16381-16417. https://doi.org/10.3390/ijms150916381
Chicago/Turabian StyleMackern-Oberti, Juan P., Fabián Vega, Carolina Llanos, Susan M. Bueno, and Alexis M. Kalergis. 2014. "Targeting Dendritic Cell Function during Systemic Autoimmunity to Restore Tolerance" International Journal of Molecular Sciences 15, no. 9: 16381-16417. https://doi.org/10.3390/ijms150916381