Akademik Veri Yönetim Sistemi
TRYPTOPHAN METABOLISM: IMPLICATIONS FOR BIOLOGICAL PROCESSES, HEALTH AND DISEASE, ss.335-360, 2015 (SCI-Expanded)
Underlying mechanisms of immune tolerance, including the characterization of antigen-presenting cells (APCs) and regulatory T (Treg) cells and the function of indoleamine 2,3-dioxygenase (IDO) activity that may play key roles in promoting operational tolerance, have been discussed in this chapter. Donor dendritic cells (DCs) migrate from graft and present the donor major histocompatibility complex (MHC) molecules to allospecific T cells. Allorecognition occurs when donor MHC molecules are processed by host APCs. Treg cells have an indispensable role in the creation of peripheral allograft tolerance; therefore, Treg cell differentiation is important to create a new T-cell repertoire. Immune tolerance primarily occurs in the thymus that is referred to as central tolerance. Elimination of self-reactive T cells and clonal anergy are two principal mechanisms of peripheral tolerance (Fig. 14.1). Allorecognition can occur by two distinct pathways; direct recognition is achieved by foreign MHC class II molecules on the surface of donor bone marrow-derived cells, and indirect recognition is executed by internalized donor class II histocompatibility molecules. Allogeneic DCs are required for both rejection and tolerance of allografts. While CD28, CD5, and CD43 contribute to negative selection of the tolerance-susceptible population, costimulatory molecule, cytotoxic T lymphocyte antigen (CTLA)-4 signaling in thymocytes may diminish the efficacy of clonal deletion. The programmed death 1 (PD-1) receptor and its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) play an important role in tolerance. Tolerogenic DCs present antigen to antigen-specific T cells but fail to deliver adequate endogenous costimulatory signals for T-cell activation and proliferation. Pathways in the B7-CD28, family of costimulatory molecules, regulate T-cell activation and tolerance. Acute rejection of vascularized solid organ allotransplants is essentially mediated through direct allorecognition, while indirect allorecognition is commonly associated with chronic rejection of transplants. The subpopulation of CD4+ T lymphocytes that coexpress the forkhead family transcription factor-3 (Foxp3) plays a unique role as Tregs. Foxp3+ Treg cells are potent mediators of dominant self-tolerance in the periphery. Interleukin (IL)-2 secretion from conventional T cells is critical for development of suppressive activity of Treg. Increased inherent IDO activity, which is the rate-limiting enzyme for the tryptophan (Trp) catabolism in transplanted cells, plays an important role in the induction of immune tolerance. IDO expression by DCs in response to interferon (IFN)-gamma stimulation may suppress T-cell responses and promote tolerance either through direct effects of Trp depletion and Trp metabolites on T cells or through the effects of IDO on DCs. Overexpression of IDO in transplanted organs can prolong allograft survival due to peripheral tolerogenic effect. Treg activation by IDO+ plasmacytoid (p) DCs requires an intact amino acid-responsive general amino acid control non-derepressible (GCN) 2 pathway in the Tregs. GCN2 and mammalian target of rapamycin (mTOR) react to amino acid deprivation. Following liver transplantation, the incidence of chronic rejection is lower than the other posttransplant organ grafts, and immunosuppression withdrawal is also successful in a high proportion of liver recipients. Liver graft acceptance results from donor antigen-specific tolerance which is demonstrated by the extension of tolerance to other grafts of donor origin.