Outlook for longer-lasting islets
Nuffield Department of Surgery, John Radcliffe Hospital, Headley Way, Oxford, UK.Nature medicine (Impact Factor: 27.36). 12/2008; 14(11):1156-7. DOI: 10.1038/nm1108-1156
Article: Donor reactive regulatory T cells[Show abstract] [Hide abstract]
ABSTRACT: Donor reactive regulatory T cells (Treg) play an important role in tolerance induction and maintenance in experimental transplant models. In this review we focus on the formation of the donor reactive Treg pool and explore the potential of these cells for therapeutic application in clinical transplantation. Donor reactive Treg can arise by both conversion of alloreactive nonregulatory cells and expansion of naturally occurring Treg (nTreg) cross-reactive with donor alloantigen but the quantitative contribution of each of these pathways is at present unclear. However, the fact that donor reactive Treg can be driven both in vivo and ex vivo by alloantigen challenge of nonregulatory precursors is encouraging as it demonstrates that the functional potential of these cells for use in clinical transplantation will not be limited by fortuitous cross-reactivity between nTreg and donor alloantigens. Treg can be generated in vivo by transplantation or alloantigen challenge in combination with Treg-permissive immunosuppression, or ex vivo by phenotypic selection or by polyclonal or antigen-specific stimulation. A number of ex-vivo protocols exist for the enrichment of Treg in the laboratory and in many cases these cells have demonstrable function both in vitro and in relevant graft-versus-host disease (GVHD) or organ transplant models. The challenge now is to understand the clinical opportunities and limitations that these populations present. Combined with appropriate immunosuppression, Treg generated/expanded in vivo or ex vivo may hold the final key to operational tolerance in clinical setting.
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ABSTRACT: Type 1 diabetes mellitus (T1DM) results from death of insulin-secreting β cells mediated by self-immune cells, and the consequent inability of the body to maintain insulin levels for appropriate glucose homeostasis. Probably initiated by environmental factors, this disease takes place in genetically predisposed individuals. Given the autoimmune nature of T1DM, therapeutics targeting immune cells involved in disease progress have been explored over the last decade. Several high-cost trials have been attempted to prevent and/or reverse T1DM. Although a definitive solution to cure T1DM is not yet available, a large amount of information about its nature and development has contributed greatly to both the improvement of patient's health care and design of new treatments. In this study, we discuss the role of different types of immune cells involved in T1DM pathogenesis and their therapeutic potential as targets and/or modified tools to treat patients. Recently, encouraging results and new approaches to sustain remnant β cell mass and to increase β cell proliferation by different cell-based means have emerged. Results coming from ongoing clinical trials employing cell therapy designed to arrest T1DM will probably proliferate in the next few years. Strategies under consideration include infusion of several types of stem cells, dendritic cells and regulatory T cells, either manipulated genetically ex vivo or non-manipulated. Their use in combination approaches is another therapeutic alternative. Cell-based interventions, without undesirable side effects, directed to block the uncontrollable autoimmune response may become a clinical reality in the next few years for the treatment of patients with T1DM.
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ABSTRACT: Islet transplantation is an alternative to pancreas transplantation to cure type 1 diabetes, but both require chronic immunosuppression, which is often accompanied by deleterious side effects. The purpose of this study was to explore prolongation of islet allograft survival by cotransplantation with myeloid-derived suppressor cells (MDSCs) without requirement of immunosuppression and determine the role of inducible nitric oxide synthase (iNOS) produced by MDSCs in immune regulation. Bone marrow cells were isolated from wild-type (WT) or iNOS mice and cultured in the presence of granulocyte-macrophage colony-stimulating factor and hepatic stellate cells (HSCs), resulting in the generation of MDSCs. WT or iNOS MDSCs were cotransplanted with islet allografts under the renal capsule of diabetic recipient mice. Addition of HSCs into DC culture promoted generation of MDSCs (instead of DCs). MDSCs had elevated expression of iNOS upon exposure to IFN-γ and inhibited T-cell responses in an MLR culture. Cotransplantation with WT MDSCs markedly prolonged survival of islet allografts, which was associated with reduced infiltration of CD8 T cells resulting from inhibited proliferative response. These effects were significantly attenuated when MDSCs were deficient in iNOS. Furthermore, iNOS MDSCs largely lost their ability to protect islet allografts. Cotransplantation with HSC-induced MDSCs significantly extends islet allograft survival through iNOS-mediated T-cell inhibition. The results demonstrate the potential use of in vitro generated MDSCs as a novel adjunctive immunotherapy for islet transplantation.
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