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）：肾移植可以挽救生命，但许多肾移植物在移植后数年因慢性抗体介导的排斥反应（CAMR）而失败。抗体可通过多种机制对移植物造成伤害：补体沉积、向移植物募集炎症细胞或直接内皮损伤。针对抗体的新治疗方式正在研究中，CAMR 的准确诊断将使患者能够被适当分类进入临床试验或进行治疗干预。目前 CAMR 的诊断标准依赖于肾活检中补体成分 C4d 的检测。最近，C4d 检测已被证明不敏感，缺失了 30% 至 70% 的 CAMR 病例。拟议的研究旨在开发一种新的算法，该算法将基于晚期移植肾活检的回顾性队列来改善 CAMR 的诊断。将使用计算机辅助数字形态测量和免疫组织化学染色的组合来突出炎症自然杀伤（NK）细胞的募集以及抗体介导损伤的主要位置（微循环）处的内皮损伤和激活标记物。回归分析将用于确定 NK 细胞浸润、内皮损伤或各种其他组织学和实验室特征是否与抗体导致的移植失败和不良预后相关。统计上显着的特征将用于构建新的 CAMR 诊断算法，随后将在前瞻性晚期活检队列和方案早期活检队列中进行验证。拟议研究的最终目标是在不可逆损伤和进展为 CAMR 之前，在亚临床阶段诊断抗体介导的损伤。针对这些患者进行治疗干预将防止与返回透析相关的发病率和死亡率，并减少第二次肾移植的数量，从而缩短肾移植的等待名单。 拟议的培训计划将为 Evan Farkash 博士提供 5 年受保护的研究时间，因为他目前担任马萨诸塞州总医院/哈佛医学院病理学临床研究员和移植生物学研究博士后研究员中心成为病理学系的终身初级教员和首席研究员。 Farkash 博士将定期接受 3 位高级教师导师 Robert Colvin 博士、David Sachs 博士和 Susan Saidman 博士的结构化建议和指导，他们都在肾移植排斥的生物学和病理生理学方面拥有丰富的专业知识。主要导师 Colvin 博士是美国国立卫生研究院 (NIH) 资助的世界著名肾脏病理学家，在培训研究和临床研究员方面拥有丰富的经验。法卡什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，并将在有丰富合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 或同等研究支持，以成为一名完全独立的医师科学家。