Chronic Antibody-Mediated Rejection of Kidney Allografts

摘要 抗体介导的机制导致急性和慢性肾移植损伤和损失仍然很差 明白对这些机制的研究由于缺乏合适的动物模型而受阻 随着供体特异性抗体（DSA）反应的启动和进展，同种异体移植物损伤的发展。 我们建立了一种新的抗体介导的排斥反应（ABMR）模型， 完全MHC不匹配的同种异体肾移植后行DSA的受者， 在野生型受体中引发的滴度。CCR 5-/-受体DSA显示移植物发生急性排斥反应 在第17 - 22天之间，具有与临床肾脏急性ABMR期间几乎相同的特征 移植物，包括相同的组织病理学和基因表达特征，表明NK细胞活化。我们有 最近证实了急性ABMR所需的同种异体肾移植物内的NK细胞活化。在 然而，在缺乏NK细胞活化的情况下，在CCR 5-/-肾同种异体移植受者中诱导的高DSA滴度是 不能介导急性ABMR，但缓慢诱导肾小管纤维化和慢性肾小球疾病发展 导致最终移植失败的损伤，类似于临床肾移植晚期失败期间观察到的损伤。 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着变化， 慢性与急性ABMR期间浸润单核细胞和巨噬细胞。慢性ABMR的发展是 也伴随着几种自身抗原的抗体的出现，这在急性期是没有观察到的。 AMR。这些结果表明，产生改变的骨髓细胞和自身抗体的关键机制 这是这种慢性病理学发展的基础，并使我们假设DSA与肾脏的结合 在缺乏NK细胞活化的情况下，同种异体移植物内皮刺激骨髓细胞募集的产生， 分化因子，使其功能偏斜，以促进自身抗体的产生和慢性 抗体介导的移植物损伤。这一假设将在三个具体目标中得到检验。具体目标1： DSA诱导移植肾内皮细胞产生髓样细胞定向因子的实验机制 在慢性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， 促进抗体介导的同种异体移植物损伤发展的移植物浸润骨髓细胞的功能。在 具体目标3我们将测试自身抗体在慢性ABMR发展中的产生和作用。的 提出的实验将利用新的和临床相关的肾移植慢性ABMR模型， 明确移植肾慢性损伤的炎性成分及其机制， 移植后。我们预计，我们的研究将继续揭示新的关键机制， 肾移植慢性ABMR的发展，并确定新的治疗靶点，以抑制或减轻这一点 病理学和改善肾移植功能和存活。

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.