Chronic Antibody-Mediated Rejection of Kidney Allografts

慢性抗体介导的同种异体肾移植排斥

基本信息

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
项目类别：
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

项目摘要

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.

抽象的抗体介导的机制导致急性和慢性同种异体移植损伤，损失仍然很差理解。缺乏适当的动物模型来阻碍对这些机制的研究随着供体特异性抗体（DSA）反应的发展并进展，同种异体移植损伤的发展。我们已经开发了一种新型的CCR5肾脏同种异体移植抗体介导的排斥反应（ABMR）模型。 DSA响应完全MHC匹配的肾脏同种异体移植物的接受者高50倍比在野生型接受者中引起的滴度。 CCR5 - / - 接受者中的DSA急剧拒绝同种异体移植物在第17至22天之间，其特征实际上与临床肾脏急性ABMR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。我们有最近证明了急性ABMR所需的肾脏同种异体移植物内的NK细胞激活。在然而，没有NK细胞激活，在CCR5 - / - 肾脏同种异体移植者中诱导的高DSA滴度是无法介导急性ABMR，但缓慢诱导了肾小管纤维化和慢性肾小球的发展导致最终的移植失败类似于临床肾移植后期失败期间观察到的损伤。我们的初步结果进一步表明了移植的表型和功能转录组的明显变化慢性与急性ABMR期间浸润单核细胞和巨噬细胞。慢性ABMR的发展是还伴随着对几种自身抗原的抗体的出现，而急性期间未观察到 AMR。这些结果表明，改变了髓样细胞和自身抗体作为关键机制的产生基本的这种慢性病理的发展，并导致我们假设DSA与肾脏结合在没有NK细胞激活的情况下，同种异体移植内皮刺激了髓样细胞募集的产生和分化因子偏向其功能以促进自身抗体的产生和慢性发展的发展抗体介导的移植物损伤。该假设将以三个特定目的进行检验。在特定目标1中，我们将 DSA诱导的肾脏同种异体移植内皮产生的测试机制指导髓样细胞的因素慢性ABMR发展过程中的招聘和功能。在特定目标2中，我们将测试角色，移植物浸润的髓样细胞的功能促进抗体介导的同种异体移植损伤的发展。在具体目的3我们将测试自动抗体在慢性ABMR发展中的生产和作用。这提出的实验将利用肾脏同种异体移植慢性ABMR的新颖和临床相关模型直接识别炎症的炎症成分及其机制介导肾移植物的慢性损伤移植后。我们预计我们的研究将继续揭示对对开发肾脏移植物慢性ABMR并确定新的治疗靶标，以抑制或减弱这一点病理学并改善肾脏移植功能和生存。