TOLERANCE IN ORGAN TRANSPLANTATION AND AUTOIMMUNE DISEASE BY T CELL IMMUNOTOXIN

T 细胞免疫毒素对器官移植和自身免疫性疾病的耐受性

• 批准号: 6290587
• 负责人: David M. Neville
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290587
• 关键词: B lymphocyte; CD3 molecule; Macaca mulatta; T lymphocyte; antileukocyte isoantibody; autoimmune disorder; diphtheria toxin; graft versus host disease; immune tolerance /unresponsiveness; immunoconjugates; immunotoxicity; kidney transplantation; recombinant proteins; tissue /cell culture; transplant rejection; transplantation immunology

The general aim of this project is to study the effects of immunotoxin induced transient T-cell depletion on the modulation of T cells from immunization responses towards tolerizing responses, and to use this knowledge for the experimental and clinical treatment of T cell driven autoimmune diseases, graft-versus-host disease, and the induction of tolerance to mismatched organ and cell transplants.We previously showed that a 2-3 day course of anti-rhesus CD3 immunotoxin constructed with CRM9, a binding site mutant of diphtheria toxin, depletes lymph node and blood T cells by 99% after a 48 hour lag period. This process was associated with a marked prolongation of survival of mismatched functioning rhesus kidney transplants and the induction of long term tolerance in about 50% of the cases without further immunosuppressive therapy. Rejections, when they occurred, were preceded by the appearance of anti-graft antibodies (done with S. Knechtle and J. Thomas). To circumvent this adverse T cell mediated B cell response that is apparently initiated during the delay in immunotoxin induced T cell killing, we have added a short course of agents that are believed to block antigen presentation such as deoxyspergualin (DSG). Long term graft survival has risen to 83% (done with J. Thomas). These grafts are tolerized as judged by the acceptance of donor skin grafts for 30 days and the rapid rejection of third party skin grafts. Congeneic pancreatic islet cell transplants in monkeys suffering from spontaneous insulin dependent diabetes have been shown to reverse diabetes as judged by returning non-fasting blood glucose and glycosylated hemoglobin values to normal in the absence of exogenous insulin. A short course of immunotoxin, methyl prednisolone and cyclosporine provide induction of stable operational tolerance to islets that has lasted over one year in one case. This is the first reported reversal of diabetes using a tolerizing protocol that does not depend on chronic immunosuppression, a process previously shown to compromise transplanted islet function (done with J. Thomas). Recombinant single chain anti-CD3 antibodies directed at both human and rhesus T cells have been developed. In eukaryote expression systems these are secreted as high affinity divalent dimers. These lack significant Fc receptor interactions and are free from the complications of cytokine release syndrome which occur with our present chemically coupled anti-CD3 immunotoxin. These recombinant antibodies form the basis of recombinant anti-CD3 immunotoxins now under development. - immunotoxin, T-cell, autoimmune, graft-versus-host disease, tolerance, CD3, CRM9, diptheria toxin, kidney transplants, deoxyspergualin (DSG)

这个项目的总体目标是研究免疫毒素诱导的暂时性T细胞耗竭对T细胞从免疫反应到耐受反应的调节作用，并将这一知识用于T细胞驱动的自身免疫性疾病、移植物抗宿主病的实验和临床治疗，以及诱导对不匹配的器官和细胞移植的耐受。我们之前的研究表明，用白喉毒素的结合位点突变CRM9构建的抗恒河猴CD3免疫毒素在48小时的滞后期后，2-3天的疗程可耗尽99%的淋巴和血液T细胞。在没有进一步免疫抑制治疗的情况下，这一过程与显著延长功能不匹配的恒河猴肾移植的存活时间和诱导约50%的病例长期耐受有关。当发生排斥反应时，在出现抗移植物抗体之前(S·克内克特尔和J·托马斯做的)。为了避开这种不利的T细胞介导的B细胞反应，这种反应显然是在免疫毒素诱导的T细胞杀伤延迟期间启动的，我们增加了一种被认为可以阻断抗原提呈的短程药物，如脱氧精灵(DSG)。移植物的长期存活率已经上升到83%(与J.Thomas一起完成)。根据供体皮肤移植物30天的接受率和第三方皮肤移植物的快速排斥反应判断，这些移植物是可以耐受的。患有自发性胰岛素依赖型糖尿病的猴子的同种胰岛细胞移植被证明可以逆转糖尿病，其判断是在没有外源胰岛素的情况下，将非空腹血糖和糖化血红蛋白恢复到正常水平。短程免疫毒素、甲基强的松龙和环孢素可诱导稳定的胰岛手术耐受，其中1例已持续一年以上。这是第一次报道使用不依赖于慢性免疫抑制的耐受性方案逆转糖尿病，这一过程以前被证明会损害移植的胰岛功能(与J.Thomas一起完成)。针对人和恒河猴T细胞的重组单链抗CD3抗体已经研制成功。在真核细胞表达系统中，它们以高亲和力二价二聚体的形式分泌。这些缺乏显着的Fc受体相互作用，并且没有细胞因子释放综合征的并发症，这些并发症发生在我们目前化学偶联的抗CD3免疫毒素上。这些重组抗体构成了目前正在开发的重组抗CD3免疫毒素的基础。-免疫毒素，T细胞，自身免疫，移植物抗宿主病，耐受性，CD3，CRM9，白喉毒素，肾移植，脱氧精氨酸(DSG)