IMMUNE ABLATION/HEMATOPOIETIC STEM CELL SUPPORT IN PATIENTS WITH MALIGNANT MS

尽管T细胞介导的髓磷脂免疫破坏被认为是一个重要的组成部分，但多发性硬化症（MS）的分子发病机制尚未完全确定。尽管免疫调节或抑制药物如强的松、环磷酰胺或干扰素有一些益处，但没有标准的治疗方法是治愈的。从20世纪60年代开始，人类骨髓移植（BMT）成功地为免疫缺陷患者（例如，严重联合免疫缺陷和Wiskott Aldrich综合征）提供了功能性免疫系统。简单来说，通过BMT治疗MS的目的是消融异常的免疫系统，然后，类似于对免疫缺陷患者使用骨髓移植，重建一个新的免疫系统，希望在供体T细胞胸腺发育过程中重新建立对相关自身表位的耐受性。这一假设得到了动物实验的支持。其中，实验性过敏性脑脊髓炎（Experimental Allergic encephalomylittis， EAE）是多发性硬化症的动物模型。EAE动物的免疫消融和同基因骨髓修复可以预防或改善临床症状，消除中枢神经系统中负责EAE的效应淋巴细胞。我们建议测试完全免疫消融后造血干细胞支持对恶性MS患者的疗效。

The molecular pathogenesis of multiple sclerosis (MS) has not been fully defined although T cell-mediated immune destruction of myelin is thought to be an important component. Despite some benefits of immune modulating or suppressive agents such as prednisone, cyclophosphamide, or B interferon, no standard therapy is curative. Beginning in the 1960's, human bone marrow transplantation (BMT) was successfully performed to provide immune deficient patients (e.g., Severe Combined Immunodeficiency and Wiskott Aldrich Syndrome) with a functional immune system. In simplistic terms, treatment of MS by means of BMT is designed to ablate an aberrant immune system and then, similar to the use of marrow transplants for immunodeficient patients, reconstitute a new immune system in the hopes of re-establishing tolerance to the relevant autoepitopes during thymic development of the donor T cells. This hypothesis is supported by animal experiments. In specific, Experimental Allergic Encephalomylitis (EAE) is an animal model for multiple sclerosis. Immune ablation and syngeneic marrow rescue in animals with EAE can prevent or ameliorate clinical symptoms and eliminate the effector lymphocytes responsible for EAE from the central nervous system. We propose to test the efficacy of complete immune ablation followed by hematopoietic stem cell support in patients with malignant MS.