MECHANISMS OF IMMUNE TOLERANCE IN A PRECLINICAL MODEL

临床前模型中的免疫耐受机制

• 批准号: 6655226
• 负责人: Judith M. Thomas
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655226
• 关键词: CD3 molecule; Macaca mulatta; T lymphocyte; artificial immunosuppression; biological models; combination chemotherapy; cooperative study; dendritic cells; flow cytometry; guanidines; homologous transplantation; immune tolerance /unresponsiveness; immunoconjugates; immunologic memory; immunosuppressive; isoantigen; kidney transplantation; monoclonal antibody; transplant rejection; transplantation immunology

Current transplant management dampens the allogeneic immune response but does not deter eventual graft loss. This imposes limitations that compromise patient survival and rehabilitation outcomes. The compelling conclusion is that chronic immunosuppressive drug therapy is not a satisfactory long-term solution. Tolerance induction has potential to offer an exit from this stalemate. The goal of Project I is to implement successful translation of tolerance to human transplantation. A novel tolerance strategy developed in an established, rhesus macaque allotransplant model using day-of-transplant tolerance induction, one with potential for translation to cadaveric donor transplantation, will be examined. Preliminary data suggest the early posttransplant period circumscribes a permissive window in which functional tolerance is induced and remains stable for periods exceeding three years. The proposed studies are designed to extend these results and elucidate immunologic mechanisms responsible for induction and maintenance of kidney allograft tolerance in this model. Peritransplant treatment with a novel immunosuppressive drug combination, F(Ab)2- or sFv alpha-CD3 immunotoxin (IT) AND Deoxyspergualin (DSG) will be used to induce tolerance. A synergy between these agents establishes an immunologically quiescent milieu, characterized by transient physical absence of T cells and mature dendritic cells (DC) in lymphoid tissues. DSG has been shown to arrest NF-kappaB-dependent DC maturation in macaques. The hypothesis of the project is that early absence and slow recovery of mature DC in lymph nodes in pivotal in preventing DC-induced activation of new T cells during peripheral repopulation. To examine this hypothesis, the IT plus DSG treated recipients will be reconstituted with mature DC of donor or recipient origin within and subsequent to this period to determine if this intervention can precipitate rejection. On a parallel track, functional and phenotypic alterations in T cell memory after IT induced T cell-specific ablation will be examined. Finally, the specificity of tolerance and the role of persisting donor antigen in maintenance of the tolerant state will be investigated. In vitro and in vivo immunologic testing will be performed to validate tolerance. Since no measurable hematopoietic microchimerism in this tolerance model has been found, a determination will be made of whether the presence of 1 degree tolerant kidney graft antigens are required to maintain a tolerant state that permits acceptance of 2 degree donor kidney, and if so, how long this requirement persists. The proposed studies will generate original information relevant to tolerance in non-human primates, i.e., the role of DC maturation in induction of tolerance and the role of antigen persistence in maintenance of tolerance. Elucidation of these mechanisms should assist translation of tolerance to humans.

目前的移植管理抑制了同种异体免疫反应，但并不能阻止最终的移植物损失。 这造成了损害患者生存和康复结果的限制。 令人信服的结论是，长期免疫抑制药物治疗并不是令人满意的长期解决方案。 宽容诱导有可能摆脱这种僵局。 项目一的目标是将耐受性成功转化为人体移植。 将检查在已建立的恒河猴同种异体移植模型中使用移植日耐受诱导开发的一种新的耐受策略，该策略具有转化为尸体供体移植的潜力。 初步数据表明，移植后早期存在一个允许窗口，在该窗口中诱导功能耐受并在超过三年的时间内保持稳定。 拟议的研究旨在扩展这些结果并阐明负责在该模型中诱导和维持肾同种异体移植耐受的免疫机制。 使用新型免疫抑制药物组合 F(Ab)2- 或 sFv α-CD3 免疫毒素 (IT) 和脱氧精胍菌素 (DSG) 进行围移植治疗，以诱导耐受。 这些药物之间的协同作用建立了一种免疫静止环境，其特征是淋巴组织中 T 细胞和成熟树突细胞 (DC) 短暂的物理缺失。 DSG 已被证明可以阻止猕猴中 NF-κB 依赖性 DC 的成熟。 该项目的假设是，淋巴结中成熟 DC 的早期缺失和缓慢恢复对于防止外周再增殖过程中 DC 诱导的新 T 细胞激活至关重要。 为了检验这一假设，IT加DSG治疗的受体将在这段时间内和之后用供体或受体来源的成熟DC进行重构，以确定这种干预是否会引发排斥反应。 在平行轨道上，将检查 IT 诱导 T 细胞特异性消融后 T 细胞记忆的功能和表型变化。 最后，将研究耐受的特异性以及持续供体抗原在维持耐受状态中的作用。 将进行体外和体内免疫学测试以验证耐受性。 由于在此耐受模型中未发现可测量的造血微嵌合，因此将确定是否需要 1 度耐受肾移植抗原的存在来维持允许接受 2 度供体肾脏的耐受状态，如果需要，如何进行这种要求长期存在。 拟议的研究将产生与非人类灵长类动物的耐受性相关的原始信息，即DC成熟在诱导耐受性中的作用以及抗原持久性在维持耐受性中的作用。 阐明这些机制应有助于将耐受性转化为人类。