DONOR-DRIVEN REGULATION IN HUMAN ALLOGRAFT ACCEPTANCE

描述(申请人提供)：人类接受肾脏和肝脏 最近发现了停用所有免疫抑制药物后的移植 与一种主动形式的外周免疫调节有关， 也可称为“旁观者”或“供体抗原相关”抑制。 旁观者抑制，这可以通过人对鼠的方式检测到 过继转移试验具有以下特点：1) 外周血单核细胞(PBMC)介导的迟发型超敏反应 (DTH)对供体细胞、可溶性同种异体抗原和 别肽，b)正常/强仅召回抗原，c)正常/强至 当存在第三方或自身抗原时召回抗原，以及d) 当供体同种异体抗原存在时，召回抗原的能力较弱/不存在；2) 未能对供体抗原作出反应和未能对召回作出反应 在供体抗原存在的情况下，可以通过包含 抗肿瘤生长因子β和/或白介素10抗体 DTH挑战位点；以及3)单个供体抗原或多肽就足够了 以触发DTH抑制。 我们建议界定这一进程的主要组成部分，包括：1) 驱动调节对效应器的各种供体可溶性抗原 反应；2)微嵌合体作为可溶性抗原和 外周淋巴组织中的直接途径(膜结合)抗原提呈 组织和宿主单核细胞系抗原提呈细胞(APC) 迟发型超敏反应；以及3)宿主同种抗原特异性的CD4+和CD8+T细胞 产生或导致产生调节性细胞因子IL-10和TGFbeta。 我们用于这些研究的PBMC来源将是人类同种异体移植的“接受者”-- 停止所有免疫抑制但仍保留移植物功能的患者。我们 假设慢性刺激是由低水平的可溶性抗原和 罕见的供者来源的白细胞推动了两个不同群体的发育 宿主T淋巴细胞：1)抗原特异性调节性T细胞和2)抗原- 其活性被调节性T细胞掩盖的特定的DTH效应T细胞- 依赖转化生长因子β和IL-10的释放。我们的目标是开发一种工作模式 供者来源的白细胞及其释放的抗原如何促进 人体宿主T调节因子与效应细胞的紧张性平衡 同种异体移植接受率。

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.