Implications of IFN-gamma-mediated tryptophan catabolism on solid organ transplantation.
The Th1-type cytokine interferon-gamma (IFN-gamma) is known as one of the most versatile players of the immune system. In transplantation immunology IFN-gamma has been shown to have contradictory effects on allograft survival via effects on both, the immune system and on the graft itself. The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO), widely distributed in mammals, is induced preferentially by IFN-gamma. IDO degrades the essential amino acid tryptophan to form N-formyl kynurenine which is subsequently converted to niacin. Recently, it has been proposed that IFN-gamma-mediated activation of IDO is critically involved in the regulation of immune responses, to establish immune-tolerance in pregnant mice upon their fetuses, or to induce T-cell unresponsiveness. Proliferation of alloreactive T-cells is thereby arrested via local tryptophan deprivation and the accumulation of toxic tryptophan catabolites. Despite growing recognition of the molecular T-cell regulatory mechanisms, the physiologic role of IDO in solid organ transplantation, however, remains unclear. Available experimental data indicate that IDO is involved in the mechanism of spontaneous donor-specific tolerance of liver grafts, and that genetic manipulation by introduction of the IDO gene into allografts is associated with prolonged survival. Furthermore, antigen-presenting cells, such as dendritic cells, can increase their expression of IDO, thus regulating immune responses. Based on these findings, the concept that cells expressing IDO can inhibit T-cell responses and hence induce tolerance has emerged as a new paradigm in immunology. Here we review the current literature on IDO in the context of transplantation and outline its potential implication as a target for tolerance induction.
Brandacher
Gerald
G
Department of General and Transplant Surgery, D. Swarovski Research Laboratory, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. gerald.brandacher@uki.at
Margreiter
Raimund
R
Fuchs
Dietmer
D
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology*; D016377:Organ Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014181:Transplantation Immunology; D014184:Transplantation, Homologous; D014364:Tryptophan / Q000276:immunology* / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D014364:Tryptophan