Indoleamine 2,3-dioxygenase gene transfer prolongs cardiac allograft survival

Abstract

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 CD8α+ cells infiltrating the graft as well as intragraft cytokine transcript levels for IFN-γ, IL-1, TNF-α, 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.