Indoleamine 2,3-dioxygenase gene transfer prolongs cardiac allograft survival.
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.
Li
Jianping
J
Centre Hospitalier Universitaire Vaudois, BH10, Lausanne 1011, Switzerland.
Meinhardt
Andrea
A
Roehrich
Marc-Estienne
ME
Golshayan
Dela
D
Dudler
Jean
J
Pagnotta
Maria
M
Trucco
Massimo
M
Vassalli
Giuseppe
G
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D016027:Heart Transplantation; D007108:Immune Tolerance / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014184:Transplantation, Homologous
D016207:Cytokines; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016572:Cyclosporine