TOLEROGENIC STEM CELL TRANSPLANTATION FOR ARTHRITIS

关节炎耐受性干细胞移植

• 批准号: 6171857
• 负责人: RONALD P MESSNER
• 金额: $ 27.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-20 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171857
• 关键词: B lymphocyte; antigen presenting cell; arthritis therapy; artificial immunosuppression; autoantibody; autoimmunity; autologous transplantation; bone marrow transplantation; cell population study; cell transplantation; collagen; cyclophosphamide; delayed hypersensitivity; disease /disorder model; disease /disorder onset; flow cytometry; helper T lymphocyte; immune tolerance /unresponsiveness; immunochemistry; laboratory mouse; nonhuman therapy evaluation; polyarthritis; stem cells

Immunoablation followed by autologous stem cell transplantation holds the promise of providing a cure for some types of severe autoimmune disease. The goal of this proposal is to examine the therapeutic potential of autologous stem cell transplantation by studying the effects of a pseudoautologous bone marrow transplant (PA-BMT) on fully-developed collagen-induced arthritis (CIA) in mice. We postulate that stem cell transplantation will provide a window of opportunity in which treatments that were formerly effective only when given before the onset of disease will now be therapeutic in mice with established disease. We will thus exploit the process of reconstitution of the immune system to reestablish the tolerance that was broken when autoimmunity was induced. The key to this process will be the use of specific treatments to render the reemerging immune system tolerant to the antigen(s) driving the autoimmune process. CIA, a well- characterized model of inflammatory polyarthritis, was chosen because it is partially responsive to immune ablation and rescue with either allogeneic or syngeneic bone marrow cells. It thus provides a model in which the proposed treatments can be judged by their ability to improve or worsen the results of transplantation alone. Preliminary experiments indicate that induction of tolerance to type II collagen in naive mice is significantly enhanced by the prior use of PA-BMT. Initial experiments will determine the optimum protocol for a PA-BMT as judged by the level of CIA activity that persists after the transplant. Subsequent experiments will evaluate the potential of post-transplant immunotherapy to eliminate the residual CIA activity that persists after transplant. The special case of antigen-specific therapy will be examined first. Protocols using collagen, which are capable of inducing tolerance if given before but not after arthritis, will be tested to determine if they regain effectiveness when used in the immediate post transplant period. The second set of experiments will explore the concept of non-CII specific immunotherapy with the aim of shifting the balance to favor tolerance rather than active response to autoantigens during rematuration of the immune system. The response of arthritis to the treatments will be correlated with studies of the level of immunologic reconstitution as well as in vivo and in vitro T and B cell responses to CII.

免疫原理随后进行自体干细胞移植有望为某些类型的严重自身免疫性疾病提供治疗方法。 该提案的目的是通过研究假学骨髓移植（PA-BMT）对完全发达的胶原蛋白诱导的关节炎（CIA）的影响来检查自体干细胞移植的治疗潜力。 我们假设干细胞移植将提供一个机会窗口，在这种机会窗口中，只有在疾病发作之前给予以前有效的治疗方法现在在患有既定疾病的小鼠中进行治疗。 因此，我们将利用免疫系统的重建过程，以重新建立诱导自身免疫性时破裂的耐受性。 该过程的关键将是使用特定的治疗方法来使耐受的免疫系统耐受抗原驱动自身免疫过程。 CIA是一种炎症性多性关节炎的特征模型，是因为它部分响应于与同种异体或合成性骨髓细胞的免疫消融和营救的部分响应。 因此，它提供了一个模型，在该模型中，可以根据其改善或恶化单独移植结果的能力来判断拟议的治疗方法。 初步实验表明，通过先前使用PA-BMT，可以显着增强对幼稚小鼠II型胶原蛋白的耐受性的显着增强。 最初的实验将确定由移植后继续存在的CIA活动水平来判断的PA-BMT的最佳协议。 随后的实验将评估移植后免疫疗法消除移植后持续存在的残留CIA活性的潜力。 将首先检查抗原特异性疗法的特殊情况。 使用胶原蛋白的方案（如果以前给予但在关节炎后不给予胶原蛋白）将进行测试，以确定它们在直接移植后期使用时是否恢复有效性。 第二组实验将探讨非CII特异性免疫疗法的概念，目的是转移平衡以偏爱容忍度，而不是在免疫系统恢复期间对自身抗原的积极反应。 关节炎对治疗的反应将与对免疫重建水​​平以及体内以及体外T和B细胞对CII的反应有关。