TOLEROGENIC STEM CELL TRANSPLANTATION FOR ARTHRITIS

关节炎耐受性干细胞移植

• 批准号: 6375121
• 负责人: RONALD P MESSNER
• 金额: $ 27.83万
• 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/6375121
• 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.

免疫消融和自体干细胞移植有望治愈某些类型的严重自身免疫性疾病。这项建议的目的是通过研究伪自体骨髓移植(PA-BMT)对小鼠充分发展的胶原性关节炎(CIA)的影响来检验自体干细胞移植的治疗潜力。我们推测，干细胞移植将提供一扇机会之窗，以前只有在疾病发作前才有效的治疗现在对已有疾病的小鼠具有治疗作用。因此，我们将利用免疫系统的重建过程来重建在诱导自身免疫时被打破的耐受性。这一过程的关键将是使用特定的治疗方法，使再生的免疫系统对推动自身免疫过程的抗原(S)具有耐受性。CIA是一种典型的炎症性多发性关节炎模型，之所以被选择，是因为它对免疫消融和异基因或同基因骨髓细胞的挽救有部分反应。因此，它提供了一个模型，在这个模型中，建议的治疗方法可以通过它们单独改善或恶化移植结果的能力来判断。初步实验表明，预先使用PA-BMT可显著增强幼鼠对II型胶原的耐受性。初步实验将根据移植后持续存在的CIA活性水平来判断PA-BMT的最佳方案。随后的实验将评估移植后免疫疗法消除移植后残留的CIA活性的潜力。将首先检查抗原特异性治疗的特殊情况。使用胶原蛋白的方案，如果在关节炎之前而不是在关节炎之后服用，能够诱导耐受性，将进行测试，以确定它们在移植后立即使用时是否重新有效。第二组实验将探索非CII特异性免疫疗法的概念，目的是在免疫系统的再成熟过程中，将平衡转向有利于耐受，而不是对自身抗原的主动反应。关节炎对治疗的反应将与免疫重建水平以及体内和体外T和B细胞对CII的反应相关。