DENDTRITIC CELLS, APOPTOTIC BODIES & TRANSPLANT TOLERAN*

描述(申请人提供)：移植急性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 抗供体异基因(Allo)抗原(Ag)。DC是专业的Ag 递呈细胞(APC)作为“乘客白细胞”将异体抗原呈递给 受体幼稚的T细胞并引发移植排斥反应。然而，DC也是 参与诱导/维持银特异性自身耐受性。的确有 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IL-10与转化生长 吞噬凋亡小体后的转化生长因子β1。我们建议测试一下 假设受者DC在与捐赠者主要互动后 组织相容性复合体(MHC)+相应的凋亡小体 细胞外环境，能够产生具有调节性的T细胞 功能。我们建议使用这种方法来诱导抗原特异性耐受。 心脏移植受者作为药物治疗的替代方案 会导致全身免疫抑制和严重的副作用。要达到 在这些目标中，我们提出以下目标。目的1：探讨三七总皂甙的作用。 凋亡小体的表型、细胞因子的合成和辅助性T细胞 (TH)-DC的体外驱动能力。我们将建立一种吞噬试验 凋亡小体对小鼠树突状细胞的现象及分子分析 牵涉其中。我们将分析合成的细胞因子的表型和模式 DC在此条件下对Th淋巴细胞亚群的影响 诱导性。目的2：研究T细胞刺激物的功能和功能。 凋亡小体对DC体内TH驱动能力的影响。我们的目的是 了解暴露在凋亡小体中的DC如何在体内调节结果 从抗原特异性免疫反应性到潜在的T细胞反应 特定于AG的耐受性。目的3：评价受者DC暴露的效果 供者MHC+凋亡小体对同种异体心脏移植存活的影响。在专注于 树突状细胞暴露于凋亡小体对同种异体免疫反应的影响 正常宿主，我们将研究它们在异体心脏移植中的作用 收件人。这一结果可能为了解凋亡小体如何 调节DC的Th驱动能力并确定其治疗潜力 DC和凋亡小体在移植耐受中的表达。

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.