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: 6111217
• 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/6111217
• 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.

这个项目的总体目标是研究 免疫毒素诱导的小鼠一过性T细胞耗竭 免疫应答对T细胞的调节作用 容忍反应，并将这一知识用于实验 T细胞驱动的自身免疫性疾病的临床治疗，移植物- 抗宿主疾病，以及对不匹配的耐受性的诱导 器官和细胞移植。我们之前展示了2-3天的时间 用CRM9，a构建的抗恒河猴CD3免疫毒素的过程 白喉毒素结合位点突变，耗尽淋巴和 血液T细胞在48小时滞后期后下降99%。这一过程是 与显著延长错配患者的生存时间有关 功能性恒河猴肾移植及其长期存活的诱导 约50%的病例没有进一步的耐受性 免疫抑制疗法。当拒绝发生时，他们是 在出现抗移植物抗体之前(用S. 克克特尔和J·托马斯)。为了避开这种不利的T细胞 介导性B细胞反应显然是在 延缓免疫毒素诱导的T细胞杀伤，我们增加了一个简短的 据信可阻断抗原提呈的药物的进程 如脱氧精灵(DSG)。移植物的长期存活率上升 到83%(与J.Thomas一起完成)。这些移植物被认为是可以容忍的 通过接受供体皮肤移植30天和快速 拒绝第三方皮肤移植。同基因胰岛细胞 患有自发性胰岛素的猴子的移植 依从性糖尿病已被证明可以逆转糖尿病 通过返回非空腹血糖和糖基化 在没有外源性胰岛素的情况下，血红蛋白值恢复到正常。一个 短程免疫毒素、甲基强的松龙和环孢素 为具有以下特征的胰岛提供稳定的操作耐受性 有一次持续了一年以上。这是第一次有报道的逆转 使用一种不依赖于 慢性免疫抑制，这一过程以前被证明 妥协移植的胰岛功能(与J.Thomas共同完成)。 针对两者的重组单链抗CD3抗体 人类和恒河猴的T细胞已经被开发出来。在真核生物中 这些表达系统以高亲和力二价体的形式分泌 二聚体。它们缺乏显著的Fc受体相互作用，并且是游离的 从发生的细胞因子释放综合征的并发症 用我们目前化学偶联的抗CD3免疫毒素。这些 重组抗体是重组抗CD3抗体的基础 免疫毒素目前正在研发中。