Article: article from journal or magazin.
Indoleamine 2,3-dioxygenase gene transfer prolongs cardiac allograft survival.
American Journal of Physiology. Heart and Circulatory Physiology
Publication types: Journal Article
Cells that express indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the catabolism of tryptophan, suppress T cell responses and promote immunological tolerance. However, their role in solid organ transplantation is incompletely understood. We analyzed T cell responses to allogeneic dendritic cells (DCs) genetically modified to express the gene encoding IDO in vitro and IDO gene transfer into the donor heart in a cardiac transplant model in vivo. Bone marrow-derived DCs transduced with the gene encoding IDO produced active IDO protein. This was associated with decreased stimulation of allogeneic T cell proliferation in the mixed leukocyte reaction in vitro. In a cardiac transplant model, adenovirus-mediated IDO gene transfer into the donor heart resulted in transgene expression predominantly in cardiomyocytes. Fischer-344 rat donor hearts transduced with the gene encoding IDO survived for longer periods of time when placed in Lewis rat recipients compared with control vector or vehicle alone [median survival times of 17 (range: 12-22) days vs. 10 (range: 8-14) and 9 (range: 8-13) days, respectively, P < 0.0001]. IDO gene transfer combined with low-dose cyclosporin A (CsA) was more effective than CsA alone (P < 0.05). Numbers of monocytes/macrophages, CD4(+) cells, and CD8alpha(+) cells infiltrating the graft as well as intragraft cytokine transcript levels for IFN-gamma, IL-1, TNF-alpha, regulated upon secretion, normal T cell expressed, and secreted/chemokine (C-C motif) ligand 5 were decreased after IDO gene transfer (P < 0.05). In conclusion, DCs genetically engineered to overexpress IDO modulate T cell alloresponses in vitro. IDO gene transfer into the donor heart attenuates acute cardiac allograft rejection. Regulation of tryptophan catabolism by means of IDO overexpression may be a useful approach in heart transplantation.
Adenoviridae/genetics, Animals, Cells, Cultured, Chemotaxis, Leukocyte, Cyclosporine/pharmacology, Cytokines/metabolism, Dendritic Cells/enzymology, Dendritic Cells/immunology, Gene Therapy/methods, Genetic Vectors, Graft Rejection/enzymology, Graft Rejection/genetics, Graft Survival/drug effects, Graft Survival/genetics, Heart Transplantation, Immune Tolerance/genetics, Immunosuppressive Agents/pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism, Lymphocyte Activation, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Models, Animal, Myocytes, Cardiac/drug effects, Myocytes, Cardiac/enzymology, Rats, Rats, Inbred F344, Rats, Inbred Lew, T-Lymphocytes/immunology, T-Lymphocytes/metabolism, Time Factors, Transduction, Genetic, Transplantation, Homologous
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