DENDRITIC CELLS, APOPTOTIC BODIES & TRANSPLANT TOLERANCE

描述（由申请人提供）： 急性同种异体移植排斥反应主要发生在 因为受体T淋巴细胞会产生强烈的特异性免疫反应， 针对供体同种异体（allo）抗原（Ag）。DC是专业的Ag 呈递细胞（APC），其作为“乘客白细胞”将allo-Ag呈递给 受体幼稚T细胞并触发移植物排斥。 然而，DC也 参与Ag特异性自身耐受的诱导/维持。有 有证据表明某些APC（巨噬细胞和可能的DC）增加了 免疫调节细胞因子白细胞介素（IL）-10和转化生长 因子（TGF）β 1摄入凋亡小体后。我们建议测试 假设 的 接收方DC， 后 相互作用 与捐助 主要 组织相容性复合体 (MHC)+凋亡小体 适当的 细胞外环境，能够产生具有调节性的T细胞， 功能我们建议采用这种方法来诱导Ag特异性耐受 在心脏移植受者中作为药物治疗的替代方案 导致全身免疫抑制和严重的副作用 达成 这些目标我们提出以下目标。目的1：探讨 凋亡小体对表型、细胞因子合成和T辅助细胞的影响 体外DC的Th驱动能力。 我们将开发一种吞噬试验， 对小鼠DC凋亡小体现象及分子进行分析 涉案我们将分析细胞因子合成的表型和模式 DC在这种条件下对Th淋巴细胞亚群的影响 诱导。 目的2：研究T细胞刺激因子的功能， 暴露于凋亡小体的DC的体内Th驱动能力。 我们的目的是 为了了解暴露于凋亡小体的DC如何在体内调节结果， T细胞对抗原特异性免疫反应的反应， Ag特异性耐受性。目的3：评价受体DC暴露后对移植瘤的影响 供体MHC+凋亡小体对心脏移植物存活的影响。在聚焦于 DC暴露于凋亡小体对同种免疫应答的影响 正常宿主，我们将研究它们在同种异体心脏移植中的作用 受惠人士这一结果可能会为凋亡小体如何在细胞内表达提供新的见解。 调节DC的Th驱动能力并确定治疗潜力 DC和凋亡小体在移植耐受中的作用。

DESCRIPTION (provided by applicant): Acute allograft rejection occurs mainly because recipient T lymphocytes mount a vigorous specific immune reaction against donor allogeneic (allo) antigens (Ag). DC are the professional Ag presenting cells (APC) that as "passenger leukocytes" present the allo-Ag to recipient naive T cells and trigger graft rejection. However, DC are also involved in the induction/maintenance of Ag-specific self-tolerance. There is evidence that certain APC (macrophages and likely DC) increase production of the immunoregulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)beta1 after ingestion of apoptotic bodies. We propose to test the hypothesis that recipient DC, after interaction with donor major histocompatibility complex (MHC)+ apoptotic bodies in the appropriate extracellular environment, are able to generate T cells with regulatory function. We propose to employ this approach to induce Ag-specific tolerance in heart allograft recipients as an alternative to pharmacological treatments that induce generalized immunosuppression and severe side effects. To reach these goals we propose the following aims. AIM 1: To investigate the effect of apoptotic bodies on the phenotype, synthesis of cytokines, and T helper (Th)-driving capacity of DC in vitro. We will develop a phagocytosis assay of apoptotic bodies for mouse DC to analyze the phenomenon and molecules involved. We will analyze the phenotype and pattern of cytokines synthesized by DC under such conditions and the impact on the subset of Th lymphocytes induced. AIM 2: To characterize the T cell stimulator's function and the Th-driving capacity in vivo of DC exposed to apoptotic bodies. Our purpose is to learn how DC exposed to apoptotic bodies can regulate, in vivo, the outcome of a T cell response from Ag-specific immune reactivity to potential Ag-specific tolerance. AIM 3: To evaluate the effect of recipient DC exposed to donor MHC+ apoptotic bodies on heart allograft survival. After focusing on the influence of DC exposed to apoptotic bodies on alloimmune responses in normal hosts, we will investigate their role in allogeneic heart graft recipients. The results may provide new insight into how apoptotic bodies can modulate the Th-driving capacity of DC and determine the therapeutic potential of DC and apoptotic bodies in transplant tolerance.