DONOR-DRIVEN REGULATION IN HUMAN ALLOGRAFT ACCEPTANCE

描述（由申请方提供）：肾脏和肝脏的人体可接受性 最近发现， 与外周免疫调节的活性形式相关， 替代地 称为“旁观者”或“供体抗原相关”抑制。 旁观者抑制，可以通过人对小鼠的 过继转移（“trans-vivo”）测定具有以下特征：1） 外周血单核细胞介导的迟发型超敏反应 (DTH)a）对供体细胞、可溶性同种异体抗原的反应弱/不存在， 同种肽，B）正常/强于单独的回忆抗原，c）正常/强于 当存在第三方或自身抗原时回忆抗原，以及d） 当供体同种异体抗原存在时， 对供体抗原无应答和对召回无应答 抗原在供体抗原存在下的逆转可以通过包含 肿瘤生长因子（TGF）β或白细胞介素（IL）-10或两者的抗体， DTH攻击位点;和3）单个供体抗原或肽就足够了 触发DTH抑制。 我们建议界定这一进程的关键组成部分，包括：1） 各种供体可溶性抗原 驱动调节而不是效应器 反应; 2）微嵌合体作为可溶性抗原和 外周淋巴细胞直接途径（膜结合）抗原呈递 组织和宿主单核细胞系抗原呈递细胞（APC）， DTH反应;和3）宿主同种异体抗原特异性CD 4+和CD 8 + T细胞， 产生或导致产生调节性细胞因子IL-10和TGF β。 我们用于这些研究的PBMC来源是人类同种异体移植物“受体”- 已停止所有免疫抑制但仍保留移植物功能的患者。我们 假设低水平可溶性抗原慢性刺激， 罕见的供体来源的白细胞驱动两个不同群体的发展 1）抗原特异性调节性T细胞和2）抗原- 特异性DTH效应T细胞，其活性被调节性T细胞掩蔽， 依赖性TGF β和IL-10释放。我们的目标是开发一个工作模型， 供体来源的白细胞及其释放的抗原如何促成 人T调节细胞与效应细胞张力平衡 同种异体移植物接受性

DESCRIPTION (provided by applicant): Human acceptance of renal and liver transplants after withdrawal of all immunosuppression has recently been found to be associated with an active form of peripheral immune regulation, alternatively termed "bystander" or "donor antigen-linked" suppression. Bystander suppression, which can be detected by means of a human-to-mouse adoptive transfer ('trans-vivo') assay, has the following features: 1) Peripheral blood mononucleocyte (PBMC)-mediated delayed type hypersensitivity (DTH) responses are a) weak/absent to donor cells, soluble alloantigens and allopeptides, b) normal/strong to recall antigens alone, c) normal/strong to recall antigens when third party or self antigens are present and d) weak/absent to recall antigens when donor alloantigens are present; 2) The failure to respond to donor antigen and the failure to respond to recall antigen in the presence of donor antigen can be reversed by the inclusion of antibodies to tumor growth factor (TGF)beta or interleukin (IL)-10 or both at the DTH challenge site; and 3) A single donor antigen or peptide is sufficient to trigger DTH inhibition. We propose to define the key components of this process, including: 1) the various donor soluble antigens which drive regulation versus effector responses; 2) microchimerism as a possible source of both soluble antigens and direct pathway (membrane-bound) antigen presentation in peripheral lymphoid tissue and host monocyte-lineage antigen-presenting cells (APC) essential for the DTH response; and 3) host alloantigen-specific CD4+ and CD8+ T cells which produce, or cause to be produced, the regulatory cytokines IL-10 and TGFbeta. Our source of PBMC for these studies will be human allograft "acceptors" - patients who have ceased all immunosuppression yet retained graft function. We hypothesize that chronic stimulation by low levels of soluble antigens and rare donor-derived leukocytes drives development of two distinct populations of host T lymphocytes: 1) antigen-specific regulatory T cells and 2) antigen- specific DTH effector T cells whose activity is masked by regulatory T cell- dependent TGFbeta and IL-10 release. Our goal is to develop a working model of how donor-derived leukocytes and the antigens they release contribute to a tonic equilibrium between host T regulator and effector cells in human allograft acceptance.