Antibody induced neutrophil and macrophage tissue pathology in renal allografts

项目摘要/摘要 抗体介导的导致急、慢性移植肾损伤和丢失的机制仍然很少 明白了。由于缺乏合适的动物模型，阻碍了对这些机制的研究 研究随着供者特异性抗体(DSA)反应的启动和移植损伤的发展 增加。我们建立了一种新的抗体介导的移植肾排斥反应(AMR)模型。 CCR5-/-完全MHC不相合肾移植后DSA滴度升高的受者 比野生型受体高出50倍。同种异体肾移植被强烈排斥 CCR5/-受体在17-22天C3d大量沉积的肾小管周围的抗体应答 水肿，中性粒细胞和巨噬细胞的渗透和激活，包括髓过氧化物酶的产生 (MPO)，排斥反应的组织病理学特征是在临床AMR中观察到的 移植。这些和我们的初步结果使我们提出了一种假设，即一个关键的机制 移植肾急性和慢性AMR的基础是中性粒细胞和 移植物中的巨噬细胞，直接导致移植物组织的急慢性损伤和靶点增加 受体抗体反应的抗原。这一假设将在三个具体目标上得到检验。具体而言 目的1鉴定和检测MPO产生细胞在抗体介导的急性排斥反应中的作用。 CCR5-/-受体的同种异体肾移植。在特定目标2中，我们将测试中性粒细胞和巨噬细胞的作用 介导的同种异体移植组织损伤在供体MHC和自身抗原特异性抗体产生中的作用 对移植肾的反应。在特定的目标3中，我们将使用B细胞耗尽策略来测试分子 抗体介导的间质纤维化和肾小管萎缩的发生机制 异体肾移植。这些研究将利用抗体介导的急性和慢性肾移植的新模型。 损伤为这些仍然是主要问题的病理机制提供了新的见解 破坏了肾移植的成功。我们预计这些研究的结果将表明新的 抑制或减轻抗体介导的移植物损伤的治疗靶点。

Project Summary / Abstract Antibody-mediated mechanisms leading to acute and chronic renal allograft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody (DSA) response is initiated and increases. We have developed a novel model of antibody-mediated rejection (AMR) of renal allografts in CCR5-/- recipients where the titers of DSA elicited in response to complete MHC-mismatched renal allografts are >50-fold higher than those elicited in wild-type recipients. The renal allografts are acutely rejected by this antibody response in CCR5-/- recipients between days 17 and 22 with heavy deposition of C3d, peritubular edema, and neutrophil and macrophage infiltration and activation including production of myeloperoxidase (MPO), histopathologic features of rejection that are characteristic of those observed during AMR in clinical transplants. These and our preliminary results have led us to propose the hypothesis that a key mechanism underlying acute and chronic AMR of renal allografts is the induced infiltration and activation of neutrophils and macrophages in the graft, which directly cause the acute and chronic graft tissue injury and increase the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will identify and test the role of MPO-producing cells during antibody-mediated acute rejection of renal allografts in CCR5-/- recipients. In Specific Aim 2 we will test the role of neutrophil and macrophage mediated allograft tissue damage in the generation of donor MHC- and autoantigen-specific antibodies in response to renal allografts. In Specific Aim 3 we will use a B cell depletion strategy to test the molecular mechanisms leading to the development of antibody-mediated interstitital fibrosis and tubular atrophy in the renal allografts. These studies will utilize novel models of antibody-mediated acute and chronic renal allograft injury to provide new insights into mechanisms underlying these pathologies that remain a major problem undermining the success of renal transplantation. We anticipate the results of these studies will indicate new therapeutic targets to inhibit or attenuate antibody-mediated graft injury.