Chronic Antibody-Mediated Rejection of Kidney Allografts

慢性抗体介导的同种异体肾移植排斥

• 批准号: 10557880
• 负责人: Robert L Fairchild
• 金额: $ 64.64万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557880
• 关键词: Acute; Allogenic; Allografting; Animal Model; Antibodies; Antibody Repertoire; Antibody Response; Antibody titer measurement; Appearance; Attenuated; Autoantibodies; Autoantigens; Binding; Blood capillaries; CCR5 gene; Cell Differentiation process; Chronic; Clinical; Development; Endothelium; Extracellular Matrix; Failure; Fibrosis; Gene Expression Profile; Generations; Goals; Graft Survival; Histopathology; Immunosuppression; Incidence; Infiltration; Inflammatory; Injury; Injury to Kidney; Investigation; Kidney; Kidney Transplantation; Knowledge; Leukocyte Trafficking; Macrophage; Mediating; Modeling; Molecular; Myeloid Cell Activation; Myeloid Cells; NK Cell Activation; Organ Transplantation; Outcome; Pathology; Phenotype; Population; Pre-Clinical Model; Production; Regimen; Renal function; Role; Serum; Solid; T-Lymphocyte; Testing; Therapeutic; Transplant Recipients; Transplantation; Tubular formation; antibody-mediated rejection; clinically relevant; donor-specific antibody; effective therapy; experimental study; graft failure; graft function; heart allograft; improved; insight; kidney allograft; monocyte; morphogens; mouse model; nephrogenesis; new therapeutic target; novel; post-transplant; recruit; response; success; synergism; therapeutically effective; transcriptome; transplantation therapy; virtual

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.

抽象的 导致急性和慢性同种异体移植肾损伤和丢失的抗体介导机制仍然很差 明白了。由于缺乏合适的动物模型来研究，对这些机制的研究受到阻碍 随着供者特异性抗体（DSA）反应的启动和进展，同种异体移植物损伤的发展。 我们开发了一种新的 CCR5-/- 肾同种异体移植物抗体介导的排斥反应 (ABMR) 模型 DSA 对完全 MHC 不匹配肾同种异体移植物的反应引起的受者比例高出 50 倍以上 高于野生型受体中引起的滴度。 CCR5-/- 受体中的同种异体移植物被 DSA 强烈排斥 第 17 天至第 22 天之间的特征与临床肾脏急性 ABMR 期间的特征几乎相同 移植物，包括相同的组织病理学和基因表达特征，表明 NK 细胞激活。我们有 最近证明，同种异体肾移植物中的 NK 细胞激活是急性 ABMR 所必需的。在 然而，在缺乏 NK 细胞激活的情况下，CCR5-/- 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，但会缓慢诱导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类似于临床肾移植晚期失败期间观察到的情况。 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 期间的浸润单核细胞和巨噬细胞。慢性 ABMR 的发展是 还伴随着针对几种自身抗原的抗体的出现，这在急性期未观察到。 AMR。这些结果表明改变的骨髓细胞和自身抗体的产生是关键机制 这种慢性病理学发展的基础，使我们推测 DSA 与肾脏结合 在没有 NK 细胞激活的情况下，同种异体移植物内皮刺激骨髓细胞募集和生成 分化因子扭曲其促进自身抗体产生和慢性病发展的功能 抗体介导的移植物损伤。该假设将在三个具体目标上进行检验。在具体目标 1 中，我们将 DSA 诱导同种异体肾内皮细胞产生定向髓细胞因子的测试机制 慢性 ABMR 发展过程中的募集和功能。在具体目标 2 中，我们将测试角色和 移植物浸润骨髓细胞的功能促进抗体介导的同种异体移植物损伤的发展。在 具体目标 3 我们将测试自身抗体的产生及其在慢性 ABMR 发展中的作用。这 拟议的实验将利用同种异体肾慢性 ABMR 的新颖且临床相关的模型来直接 识别晚期肾移植慢性损伤的炎症成分及其机制 移植后。我们预计我们的研究将继续揭示对 肾移植慢性 ABMR 的发展并确定新的治疗靶点来抑制或减弱这种情况 病理学并改善肾移植功能和存活率。