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.
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