TOLEROGENIC STEM CELL TRANSPLANTATION FOR ARTHRITIS

自体干细胞移植后的免疫消融有望为某些类型的严重自身免疫性疾病提供治疗。 本提案的目的是通过研究假自体骨髓移植（PA-BMT）对小鼠完全发展的胶原诱导性关节炎（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之窗，以前只有在疾病发作前给予有效的治疗，现在将在已确诊疾病的小鼠中得到治疗。 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破坏的耐受性。 这一过程的关键将是使用特定的治疗方法，使重新出现的免疫系统对驱动自身免疫过程的抗原具有耐受性。 选择CIA，一种充分表征的炎性多关节炎模型，因为它对免疫消融和同种异体或同系骨髓细胞的拯救有部分反应。 因此，它提供了一个模型，其中所提出的治疗方法可以通过其单独改善或恶化移植结果的能力来判断。 初步的实验表明，诱导耐受性II型胶原蛋白在幼稚小鼠显着增强了事先使用PA-BMT。 最初的实验将确定PA-BMT的最佳方案，通过移植后持续存在的CIA活性水平来判断。 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。 抗原特异性治疗的特殊情况将首先检查。 使用胶原蛋白的方案，如果在关节炎之前而不是之后给予，则能够诱导耐受性，将进行测试以确定它们在移植后立即使用时是否恢复有效性。 第二组实验将探索非CII特异性免疫疗法的概念，目的是在免疫系统再成熟期间将平衡转移到有利于耐受性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反应的研究相关。

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.