Role of integrin CD11b in delayed graft function and allorejection

整合素 CD11b 在移植物功能延迟和同种异体排斥中的作用

• 批准号: 9809349
• 负责人: M. AMIN ARNAOUT
• 金额: $ 24.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809349
• 关键词: Acute; Adhesions; Alloantigen; Allogenic; Allografting; Animals; Antibodies; Autologous; Bacterial Antigens; Binding; Biopsy; Blood Coagulation Factor; Cell Adhesion Molecules; Cells; Chronic; Clinical; Clinical Trials; Complement 3d; Data; Diabetes Mellitus; Exposure to; Failure; Fibrinogen; Fibrosis; Free Radicals; Functional disorder; GTP-Binding Proteins; Generations; Graft Survival; Heterogeneity; Homing; Human; ITGAM gene; ITGB2 gene; Immune; Immune response; Immunologic Receptors; Immunosuppression; In Vitro; Individual; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Integrins; Intercellular adhesion molecule 1; Interferon Type II; Interleukin-18; Interleukin-6; Intervention; Ischemia; Kidney; Kidney Failure; Kidney Transplantation; Laboratory mice; Leukocytes; Ligands; Link; MHC Class I Genes; Macrophage-1 Antigen; Mediating; Mediator of activation protein; Modeling; Monoclonal Antibodies; Mus; Natural Immunity; Organ; Outcome; Pathologic; Peptide Hydrolases; Phagocytosis; Phase; Physiological; Play; Population; Primates; Process; Production; RANTES; Recovery; Reperfusion Injury; Reperfusion Therapy; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Stabilizing Agents; Superoxides; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Transplant Recipients; Transplantation; Viral Antigens; adaptive immunity; adverse outcome; allograft rejection; clinically relevant; cross reactivity; cytokine; delayed graft function; effective intervention; effective therapy; immunogenicity; implantation; injured; isoimmunity; kidney allograft; migration; monocyte; neoantigens; neutrophil; nonhuman primate; preservation; prevent; recruit; species difference; tissue repair; transplant model

Project Summary/Abstract Delayed graft function (DGF) is a manifestation of ischemia-reperfusion injury (IRI) in the transplanted kidney allograft. DGF is an important risk factor in T-cell or antibody-mediated biopsy-proven acute rejection, and the strongest risk factor for chronic allograft dysfunction, exceeding even that of pre-transplant diabetes. IRI is an acute inflammatory response mediated by the recipient's activated innate immune cells that infiltrate the ischemic organ following reperfusion. Previous efforts to limit IRI, conducted primarily in rodents, have targeted individual proinflammatory mediators and showed promise in rodents, but this approach was less effective in large animals and failed in human trials. We have demonstrated that the archetypal innate immune receptor leukocyte integrin CD11b/CD18 mediates IRI in native nonhuman primate (NHP) kidneys, and that a first-in- class anti-CD11b monoclonal antibody (mAb107) protected IRI native kidneys from otherwise irreversible kidney failure. The main objective of this exploratory R21 is to evaluate the effect of limiting IRI with mAb107 on DGF in our well-studied NHP kidney transplant model. We have also shown that the recipient's innate alloreactive memory T cells present in primates but absent in laboratory mice, play a critical role in allograft rejection. Our preliminary data show that these cells express CD11b, and are inhibited by mAb107 in vitro. Therefore, a second objective of this study is to evaluate the effect of mAb107 on the proinflammatory functions of these alloreactive cells in NHP transplant recipients. These studies should help elucidate the mechanisms linking innate DGF, rejection and allograft outcome, and may help define an effective approach to limiting the progressive fibrosis currently observed clinically in 65% of renal allografts.

项目总结/摘要 移植肾功能延迟恢复（DGF）是移植肾缺血再灌注损伤（IRI）的表现 同种异体移植DGF是T细胞或抗体介导的经活检证实的急性排斥反应的重要危险因素， 慢性移植物功能障碍的最强危险因素，甚至超过移植前糖尿病。IRI是一个 急性炎症反应介导的受体的激活的先天免疫细胞，浸润 再灌注后缺血器官。以前的努力，以限制IRI，主要是在啮齿动物进行，有针对性的 在啮齿类动物中，这种方法显示出希望，但在 在大型动物身上试验失败。我们已经证明，原型先天免疫受体 白细胞整合素CD 11b/CD 18介导天然非人灵长类动物（NHP）肾脏中的IRI， 类抗CD 11b单克隆抗体（mAb 107）保护IRI天然肾脏免受其他不可逆的 肾衰竭该探索性R21的主要目的是评价用mAb 107限制IRI的效果 在我们研究充分的NHP肾移植模型中对DGF的影响。我们还证明了接受者的先天性 同种异体反应性记忆T细胞存在于灵长类动物中，但在实验室小鼠中不存在，在同种异体移植中起关键作用。 排斥反应我们的初步数据表明，这些细胞表达CD 11b，并在体外被mAb 107抑制。 因此，本研究的第二个目的是评估mAb 107对促炎性细胞因子的作用。 这些同种异体反应性细胞在NHP移植受体中的功能。这些研究应该有助于阐明 机制连接先天性DGF，排斥反应和同种异体移植物的结果，并可能有助于确定一种有效的方法， 限制了目前临床上在65%的同种异体肾移植物中观察到的进行性纤维化。