C4d-independent diagnosis of chronic antibody mediated renal allograft rejection

慢性抗体介导的肾同种异体移植排斥反应的 C4d 独立诊断

• 批准号: 8618038
• 负责人: Evan A Farkash
• 金额: $ 14.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618038
• 关键词: Address; Affinity; Algorithms; Antibodies; Biological Assay; Biology; Biopsy; Budgets; CD3 Antigens; CD34 gene; Calcineurin; Calcineurin inhibitor; Categories; Cells; Cellularity; Characteristics; Chronic; Clinical; Clinical Trials; Collaborations; Complement; Computer Assisted; Computers; Deposition; Detection; Development; Diagnosis; Diagnostic; Dialysis procedure; Disease; Endothelium; Environment; Equipment and Supplies; FCGR3B gene; Faculty; Fc Receptor; Functional disorder; Funding; General Hospitals; Goals; Graft Rejection; Graft Survival; Histologic; Image; Immune system; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Isoantibodies; Kidney; Kidney Transplantation; Laboratories; Life; Location; Massachusetts; Mediating; Mediator of activation protein; Mentors; Microcirculation; Modality; Molecular; Molecular Profiling; Morbidity - disease rate; Multivariate Analysis; NCAM1 gene; Natural Killer Cells; Outcome; Pathologist; Pathology; Patients; Pattern; Physicians; Population; Positioning Attribute; Postdoctoral Fellow; Protocols documentation; ROC Curve; Regression Analysis; Research; Research Personnel; Research Support; Research Training; Risk Factors; Role; Scientist; Staging; Staining method; Stains; Structure; Surrogate Endpoint; System; Techniques; Testing; Therapeutic Intervention; Time; Toxic effect; Training; Transcript; Transplantation; Triage; United States National Institutes of Health; Up-Regulation; VWF gene; Validation; Vascular Endothelial Growth Factor Receptor; Waiting Lists; allograft rejection; base; cohort; complement C4d; digital; graft failure; improved; kidney allograft; laboratory facility; macrophage; medical schools; morphometry; mortality; novel; novel diagnostics; novel therapeutics; prevent; prospective; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Kidney transplantation is life-saving, but many kidney grafts fail years after transplantation from chronic antibody mediated rejection (CAMR). Antibodies can cause harm to grafts via variety of mechanisms: deposition of complement, recruitment of inflammatory cells to the graft, or direct endothelial injury. New therapeutic modalities targeting antibodies are under investigation, and accurate diagnosis of CAMR would enable patients to be appropriately triaged into clinical trials or for therapeutic intervention. Te current diagnostic criteria for CAMR relies on detection of the complement component C4d in a kidney biopsy. Recently, the C4d assay has been shown to be insensitive, missing between 30% and 70% of CAMR cases. The proposed research aims to develop a novel algorithm that will improve the diagnosis of CAMR based on a retrospective cohort of late transplant kidney biopsies. A combination of computer-aided digital morphometry and immunohistochemical stains will be used to highlight the recruitment of inflammatory natural killer (NK) cells and endothelial injury and activation markers at the primary location of antibody mediated injury, the microcirculation. Regression analysis will be used to determine whether NK cell infiltration, endothelial injury, or a variety of additional histologic and laboratory characteristics are associated with graft failure from antibodies and poor outcome. Statistically significant features will be used to assemble a new diagnostic algorithm for CAMR, which will be subsequently validated in both a prospective late biopsy cohort and a protocol early biopsy cohort. The ultimate goal of the proposed research is to enable diagnosis of antibody mediated injury during its subclinical stage, before irreversible injury and progression to CAMR. Targeting these patients for therapeutic intervention would prevent the morbidity and mortality associated with return to dialysis, and reduce the number of second kidney transplants, therefore shortening the kidney transplant waiting list. The proposed training plan will provide 5 years of protected research time for Dr. Evan Farkash, as he transitions from his current role as a clinical fellow in pathology at Massachusetts General Hospital/Harvard Medical School and post-doctoral research fellow in the Transplantation Biology Research Center into a tenured junior faculty position and primary investigator in the Department of Pathology. Dr. Farkash will receive regular structured advice and guidance from 3 senior faculty mentors, Dr. Robert Colvin, Dr. David Sachs, and Dr. Susan Saidman, all of whom have extensive expertise in the biology and pathophysiology of renal transplant rejection. The primary mentor, Dr. Colvin, is NIH funded, a world-renowned renal pathologist, and has an extensive track record of training research and clinical fellows. Dr. Farkash has access to laboratory facilities, equipment, and supplies to enable him to address the experimental questions within the confines of the proposed budget, and will be performing the research in an environment with abundant opportunities for collaboration. The ultimate goal of Dr. Farkash's training is to apply for a R01 or equivalent research support with the aim of becoming a fully independent physician-scientist.

描述（由申请人提供）：肾脏移植是挽救生命的，但是许多肾脏移植物在慢性抗体介导的排斥反应（CAMR）后几年失败。抗体可能通过多种机制对移植物造成伤害：补体沉积，炎症细胞募集到移植物或直接内皮损伤。靶向抗体的新治疗方法正在研究中，对CAMR的准确诊断将使患者能够适当地进行临床试验或治疗干预。 CAMR的当前诊断标准依赖于肾脏活检中补体成分C4D的检测。最近，C4D分析已显示出不敏感，缺少30％至70％的CAMR病例。拟议的研究旨在开发一种新型算法，该算法将根据后期移植肾活检的回顾性队列改善CAMR的诊断。在抗体介导的损伤的主要位置，将计算机辅助数字形态计和免疫组织化学染色的组合用于突出炎症天然杀伤（NK）细胞以及内皮损伤和激活标记物的募集。回归分析将用于确定NK细胞浸润，内皮损伤或多种其他组织学和实验室特征是否与抗体和效果不佳的移植物失败有关。统计学上的显着特征将用于组装CAMR的新诊断算法，随后将在前瞻性的晚活检队列和协议早期活检队列中验证。拟议研究的最终目标是在不可逆的损伤和向CAMR进展之前诊断出抗体介导的损伤。针对这些患者进行治疗干预将防止与透析恢复有关的发病率和死亡率，并减少第二肾移植的数量，从而缩短肾脏移植等待名单。 拟议的培训计划将为Evan Farkash博士提供5年保护的研究时间，因为他从目前在马萨诸塞州综合医院/哈佛医学院的病理学临床研究员和移植生物学研究中心的博士后研究员转变为病理学系的终身初级教师职位和病理学系的主要研究员。 Farkash博士将获得3位高级教师Robert Colvin博士，David Sachs博士和Susan Saidman博士的定期结构化建议和指导，他们在肾脏移植拒绝的生物学和病理生理学方面都有广泛的专业知识。主要导师Colvin博士是NIH资助的，是一名世界知名的肾脏病理学家，并具有培训研究和临床研究员的广泛记录。 Farkash博士可以使用实验室设施，设备和用品，使他能够在拟议预算的范围内解决实验问题，并将在具有丰富协作机会的环境中进行研究。 Farkash博士培训的最终目标是申请R01或同等的研究支持，以成为完全独立的医师科学家。