T CELL ACTIVATING CYTOKINES IN TOLERANCE INDUCTION

点击翻译按钮获取中文摘要

Transplantation tolerance can be defined as indefinite allograft survival in the absence of continuous immunosuppressive therapy. Proposed immunologic mechanisms of tolerance induction include deletion and/or anergy of the alloreactive T cell population. The in vivo role of cytokines in these processes are not well understood. The underlying thesis of this proposal is that T cell-activating cytokines produced during the primary alloimmune response are required for the induction of long-term allograft survival and transplantation tolerance. We hypothesize that IFNgamma contributes to the induction of clonal anergy by limiting the proliferation of activated T lymphocytes, while IL-2 contributes to clonal deletion by promoting the apoptosis of activated T lymphocytes. To test this hypothesis, we will establish an adoptive transfer model in which T cell receptor for antigen transgenic (TCR-tg) CD8+ T lymphocytes (2C cells) which react to a single allo-antigen (the murine L/d MHC class I molecule), are injected into wild-type syngeneic recipients. This maneuver produces an allo-antigen/MHC-specific T cell population within the recipient that is large enough to be detected by flow cytometry but small enough to behave in a near physiological manner when exposed to an L/d-bearing allograft. In specific aim 1, we propose to monitor the clonal kinetics (expansion and contraction) and functional characteristics of adoptively transferred 2C cells during a productive alloimmune response (acute rejection of a vascularized cardiac allograft) and following tolerance induction. Combined treatment of allograft recipients with donor-specific splenocyte transfusion and T cell costimulation blockade will be employed to induce transplantation tolerance. In specific aim 2, we propose to study the role of IFNgamma in the induction of clonal T cell anergy by comparing the behavior of adoptively transferred wild-type 2 C and IFN gamma-/- 2C T lymphocytes during allo-immunity and following tolerance induction. In specific aim 3, we propose to study the role of IL-2 in the induction of clonal T cell deletion/reduction by comparing the behavior of adoptively transferred wild-type 2C and IL-2-/- 2C T lymphocytes during allo-immunity and following tolerance induction. The clinical relevance of these studies is underscored by the possibility that conventional immunosuppressive gents which inhibit IFNgamma and IL-2 production may interfere with achieving tolerance in the transplant recipient.