Med. Sci.2014, 2(2), 82-97; doi:10.3390/medsci2020082 - published online 14 April 2014 Show/Hide Abstract
Abstract: Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.
Med. Sci.2014, 2(2), 70-81; doi:10.3390/medsci2020070 - published online 26 March 2014 Show/Hide Abstract
Abstract: Obtaining human tumor cell lines from fresh tumors is essential to advance our understanding of antitumor immune surveillance mechanisms and to develop new ex vivo strategies to generate an efficient anti-tumor response. The present study delineates a simple and rapid method for efficiently establishing primary cultures starting from tumor samples of different types, while maintaining the immuno-histochemical characteristics of the original tumor. We compared two different strategies to disaggregate tumor specimens. After short or long term in vitro expansion, cells analyzed for the presence of malignant cells demonstrated their neoplastic origin. Considering that tumor cells may be isolated in a closed system with high efficiency, we propose this methodology for the ex vivo expansion of tumor cells to be used to evaluate suitable new drugs or to generate tumor-specific cytotoxic T lymphocytes or vaccines.
Med. Sci.2014, 2(1), 51-69; doi:10.3390/medsci2010051 - published online 20 February 2014 Show/Hide Abstract
Abstract: Tracking vaccine components from the site of injection to their destination in lymphatic tissue, and simultaneously monitoring immune effects, sheds light on the influence of vaccine components on particle and immune cell trafficking and therapeutic efficacy. In this study, we create a hybrid particle vaccine platform comprised of porous silicon (pSi) and superparamagnetic iron oxide nanoparticles (SPIONs). The impact of nanoparticle size and mode of presentation on magnetic resonance contrast enhancement are examined. SPION-enhanced relaxivity increased as the core diameter of the nanoparticle increased, while encapsulation of SPIONs within a pSi matrix had only minor effects on T2 and no significant effect on T2* relaxation. Following intravenous injection of single and hybrid particles, there was an increase in negative contrast in the spleen, with changes in contrast being slightly greater for free compared to silicon encapsulated SPIONs. Incubation of bone marrow-derived dendritic cells (BMDC) with pSi microparticles loaded with SPIONs, SIINFEKL peptide, and lipopolysaccharide stimulated immune cell interactions and interferon gamma production in OT-1 TCR transgenic CD8+ T cells. Overall, the hybrid particle platform enabled presentation of a complex payload that was traceable, stimulated functional T cell and BMDC interactions, and resolved in cellular activation of T cells in response to a specific antigen.
Med. Sci.2014, 2(1), 37-50; doi:10.3390/medsci2010037 - published online 18 February 2014 Show/Hide Abstract
Abstract: Effects of tobacco smoke on hematologic derangements have received little attention. This study employed a mouse model of cigarette smoke exposure to explore the effects on bone marrow niche function. While lung cancer is the most widely studied consequence of tobacco smoke exposure, other malignancies, including leukemia, are associated with tobacco smoke exposure. Animals received cigarette smoke exposure for 6 h/day, 5 days/week for 9 months. Results reveal that the hematopoietic stem and progenitor cell (HSPC) pool size is reduced by cigarette smoke exposure. We next examined the effect of cigarette smoke exposure on one supporting cell type of the niche, the mesenchymal stromal cells (MSCs). Smoke exposure decreased the number of MSCs. Transplantation of naïve HSPCs into irradiated mice with cigarette smoke exposure yielded fewer numbers of engrafted HSPCs. This result suggests that smoke-exposed mice possess dysfunctional niches, resulting in abnormal hematopoiesis. Co-culture experiments using MSCs isolated from control or cigarette smoke-exposed mice with naïve HSPCs in vitro showed that MSCs from cigarette smoke-exposed mice generated marked expansion of naïve HSPCs. These data show that cigarette smoke exposure decreases in vivo MSC and HSC number and also increases pro-proliferative gene expression by cigarette smoke-exposed MSCs, which may stimulate HSPC expansion. These results of this investigation are clinically relevant to both bone marrow donors with a history of smoking and bone marrow transplant (BMT) recipients with a history of smoking.
Med. Sci.2014, 2(1), 23-36; doi:10.3390/medsci2010023 - published online 28 January 2014 Show/Hide Abstract
Abstract: Chimeric antigen receptors (CARs) are increasingly being used in clinical trials to treat a variety of malignant conditions and recent results with CD19-specific CARs showing complete tumor regressions has sparked the interest of researchers and the public alike. Traditional CARs have been generated using single-chain variable fragments (scFv), often derived from murine monoclonal antibodies, for antigen specificity. As the clinical experience with CAR T cells grows, so does the potential for unwanted immune responses against the foreign transgene. Strategies that may reduce the immunogenicity of CAR T cells are humanization of the scFv and the use of naturally occurring receptor ligands as antigen-binding domains. Herein, we review the experience with alternatively designed CARs that contain receptor ligands rather than scFv. While most of the experiences have been in the pre-clinical setting, clinical data is also emerging.
Med. Sci.2014, 2(1), 1-22; doi:10.3390/medsci2010001 - published online 27 December 2013 Show/Hide Abstract
Abstract: The mechanisms by which natural dietary compounds exert their antitumor effects have been the focus of a large number of research efforts in recent years. Induction of apoptosis by inhibition of cell proliferative pathways is one of the common means of cell death employed by these dietary compounds. However, agents that can activate an antitumor immune response in addition to a chemotherapeutic effect may be useful adjuvants or alternative therapies for the treatment of cancer. The focus of this review is to highlight representative dietary compounds, namely Withania somnifera, Panax ginseng, curcumin and resveratrolwith special emphasis on their antitumor immune mechanism of action. Each of these dietary compounds and their sources has a history of safe human use as food or in herbal medicine traditions, potentially making them ideal therapeutics. Here we report the recent advances in the cellular immune mechanisms utilized by these compounds to induce antitumor immunity. Taken together, these findings provide a new perspective for exploiting novel dietary compounds as chemoimmunotherapeutic anti-cancer agents.