T CELL ACTIVATING CYTOKINES IN TOLERANCE INDUCTION

移植耐受可以定义为不确定的同种异体移植物存活 在没有持续免疫抑制治疗的情况下。提出 耐受诱导免疫机制包括缺失和/或 同种异体反应性T细胞群体的无反应性。体内作用 细胞因子在这些过程中的作用尚不清楚。底层 该建议的论点是T细胞活化细胞因子产生 在初次同种免疫应答期间， 长期同种异体移植物存活和移植耐受。我们假设 IFN-γ通过限制细胞增殖， 活化的T淋巴细胞的增殖，而IL-2有助于 通过促进活化的T淋巴细胞的凋亡而克隆性缺失。到 为了验证这一假设，我们将建立一个过继转移模型， 其中T细胞抗原受体转基因（TCR-tg）CD 8 + T淋巴细胞 (2C细胞），其与单一同种异体抗原（鼠L/d MHC类）反应 I分子）注射到野生型同基因受体中。这 操作产生同种抗原/MHC特异性T细胞群， 受体大到足以通过流式细胞术检测，但 小到足以在接近生理学的方式下表现出来， 带L/D的同种异体移植物。在具体目标1中，我们建议监测克隆 动力学（膨胀和收缩）和功能特性 在生产性同种免疫应答期间过继转移的2C细胞 （血管化心脏同种异体移植物的急性排斥反应）和以下 耐受诱导同种异体移植受者的联合治疗 供体特异性脾细胞输注和T细胞共刺激阻断 将用于诱导移植耐受。在具体目标2中， 我们建议研究IFN γ在诱导克隆性T细胞中的作用， 通过比较过继转移的野生型2C 和IFN γ-/- 2C T淋巴细胞在同种免疫和以下 耐受诱导在具体目标3中，我们建议研究 IL-2在诱导克隆性T细胞缺失/减少中的作用 过继转移的野生型2C和IL-2-/-2C T的行为 淋巴细胞在同种免疫和耐受诱导后。的 这些研究的临床相关性被以下可能性所强调： 抑制IFN γ和IL-2的常规免疫抑制剂 生产可能会干扰移植物的耐受性 收件人。

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.