Study of the effect of indoleamine 2,3-dioxygenase on murine mixed lymphocyte reactions and skin allograft rejection

Abstract

ACUTE REJECTION of allografts is mediated by the coordinated infiltration and effector functions of alloantigen-specific T cells. After infiltration of transplanted allografts, host T cells are activated to produce proinflammatory cytokines and to express cytolytic activities that mediate destruction of the graft tissue. It is known that interferon(INF) is often produced and detected in allografts during rejection. Although INFup-regulates MHC molecule expression and enhances alloantigen presentation in vitro, it is not required for acute rejection of fully allogeneic (MHC class I–disparate and MHC class II–disparate) grafts. Instead, INFhas an essential immunoregulatory function in vivo. INFcan facilitate the induction of long-term allograft survival and tolerance to protein antigens partly by limiting the proliferation of activated T lymphocytes. Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the L-tryptophan-kynurenine pathway that converts the essential amino acid, Ltryptophan (L-TRP), to N-formylkynurenine in mammalian extrahepatic tissues. It recently was proposed that IDO-mediated immunosuppression might prevent rejection of the fetus by the maternal T-cell response. Although several studies have circumstantially linked IDO induction to certain anti-proliferative and antimicrobial effects of immune stimuli, different and potentially detrimental consequences of IDO induction also have been proposed. Although the mechanism of IDO induction in vivo is unclear, it is widely accepted that IDO is up-regulated by INF– dependent and INF– independent mechanisms, and down-regulated by interleukin (IL)-4 and TGF. It has not yet been established, however, whether the physiological role of IDO regulation by these cytokines is beneficial or detrimental, nor whether this enzyme has an effect on allograft rejection. Several studies suggest that INFinduction of IDO exerts anti-microbial and anti-proliferative effects, possibly by depleting L-TRP. By treating skin allograft mice with 1-methyl-DL-tryptophan, which competes with L-TRP for IDO, we tested whether IDO might play an important role in the skin allograft rejection as a mechanism for regulating T-cell responses after producing INF. MATERIALS AND METHODS Mice BALB/c (H-2), C57BL/6 (H-2), B6.C-H2bm1, and B6.C-H2bm12 female mice, aged 6 to 8 weeks, were purchased from the Animal Production Area, NCI-Frederick (Frederick, Md, USA).