Chronic Antibody-Mediated Rejection of Kidney Allografts

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来研究，阻碍了对这些机制的研究 随着供者特异性抗体(DSA)反应的启动和进展，同种异体移植损伤的发生发展。 我们在CCR5-/-中建立了一种新的抗体介导的移植肾排斥反应(ABMR)模型 完全MHC不相合的肾移植后出现DSA反应的受者的风险增加了50倍 比野生型受体产生的滴度更高。CCR5-/-受者的同种异体移植物被DSA强烈拒绝 17天至22天之间，其特征与临床肾脏急性ABMR期间的特征基本相同 移植物，包括相同的组织病理学和表明NK细胞激活的基因表达特征。我们有 最近证实移植肾中的NK细胞活化是急性ABMR所必需的。在 然而，在没有NK细胞激活的情况下，CCR5/-肾移植受者诱导的高DSA滴度是 不能介导急性ABMR，但缓慢地导致肾小管纤维化和慢性肾小球的发展 导致最终移植失败的损伤，与临床肾移植晚期失败时所观察到的损伤相似。 我们的初步结果进一步表明移植物的表型和功能转录组发生了显著的变化。 慢性ABMR与急性ABMR时单核细胞和巨噬细胞的渗入。慢性ABMR的进展 还伴随着几种自身抗原的抗体的出现，这种抗体在急性发作期间没有观察到 AMR.这些结果表明，髓系细胞和自身抗体的产生是关键机制。 在这种慢性病理发展的基础上，并使我们假设DSA与肾脏结合 无NK细胞激活的同种异体血管内皮细胞刺激髓系细胞募集和产生 分化因子在促进自身抗体产生和慢性粒细胞白血病发生发展中的作用 抗体介导的移植物损伤。这一假设将在三个具体目标上得到检验。在具体目标1中，我们将 DSA诱导移植肾内皮细胞产生髓系细胞导向因子的实验机制 慢性ABMR发展过程中的招募和功能。在具体目标2中，我们将测试角色和 移植物浸润性髓系细胞促进抗体介导的同种异体移植物损伤的功能。在……里面 具体目标3我们将测试自身抗体的产生及其在慢性ABMR发病中的作用。这个 拟议的实验将利用新的和临床相关的移植肾慢性ABMR模型直接 晚期肾移植慢性损伤的炎性成分及其机制研究 移植后。我们预计，我们的研究将继续揭示关键的新机制 移植肾慢性ABMR的发展及寻找新的治疗靶点来抑制或减轻这种情况 病理和改善移植肾功能和存活率。

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 progresses. We have developed a novel model of antibody-mediated rejection (ABMR) of kidney allografts in CCR5-/- recipients where DSA elicited in response to complete MHC-mismatched renal allografts are >50-fold higher than the titers elicited in wild-type recipients. The allografts are acutely rejected by the DSA in CCR5-/- recipients between days 17 and 22 with features that are virtually identical to those during acute ABMR of clinical kidney grafts, including identical histopathology and gene expression signatures indicating NK cell activation. We have recently demonstrated NK cell activation within the kidney allografts that is required for acute ABMR. In the absence of NK cell activation, however, the high DSA titers induced in CCR5-/- kidney allograft recipients are incapable of mediating acute ABMR but slowly induce development of tubular fibrosis and chronic glomerular injury that leads to eventual graft failure similar to that observed during late failure of clinical kidney transplants. Our preliminary results further indicate marked changes in the phenotype and functional transcriptome of graft infiltrating monocytes and macrophages during chronic vs. acute ABMR. Development of the chronic ABMR is also accompanied by the appearance of antibodies to several autoantigens that is not observed during acute AMR. These results suggest the generation of altered myeloid cells and autoantibodies as key mechanisms underlying the development of this chronic pathology and have led us to hypothesize that DSA binding to kidney allograft endothelium in the absence of NK cell activation stimulates production of myeloid cell recruitment and differentiation factors that skew their function to promote autoantibody production and development of chronic antibody-mediated graft injury. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will test mechanisms of DSA-induced kidney allograft endothelial production of factors directing myeloid cell recruitment and function during development of chronic ABMR. In Specific Aim 2 we will test the role and functions of graft infiltrating myeloid cells that promote development of antibody-mediated allograft injury. In Specific Aim 3 we will test the production and role of auto-antibodies in the development of chronic ABMR. The proposed experiments will utilize novel and clinically relevant models of kidney allograft chronic ABMR to directly identify the inflammatory components and their mechanisms mediating chronic injury of the kidney grafts late after transplant. We anticipate that our studies will continue to reveal novel mechanisms critical to the development of kidney graft chronic ABMR and to identify new therapeutic targets to inhibit or attenuate this pathology and improve kidney graft function and survival.