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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3415    most recent 00532.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Li, J. Articles by Vassalli, G. Search for Related Content PubMed PubMed Citation Articles by Li, J. Articles by Vassalli, G.

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

Departments of ¹Cardiology, ²Microbiology, ³Nephrology, and ⁴Rheumatology and ⁵Transplantation Center, Centre Hospitalier Universitaire Vaudois and Université de Lausanne, Faculté de Biologie et Médicine, Lausanne, Switzerland; and ⁶Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted 25 September 2007 ; accepted in final form 9 October 2007

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 CD8⁺ cells infiltrating the graft as well as intragraft cytokine transcript levels for IFN-, IL-1, TNF-, 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.

dendritic cells; transforming growth factor-β; regulated on activation, normal T-cell expressed and secreted/C-C chemokine ligand 5