Immune Tolerance after Severe Immunosuppression and Stem Cell Rescue for JIA

描述（由申请人提供）： 这项计划拨款提案将启动拟议的临床试验，严重免疫抑制后的免疫耐受与干细胞救援JIA，这是在下面的摘要中描述。 全身性关节炎是幼年特发性关节炎（JIA）的一种形式，其特征在于关节外 表现为发热、皮疹、器官肿大和心包炎。它是JIA最严重的类型，预后最差，通常是难治性的，导致严重的关节破坏和残疾以及死亡率增加。诱导难治性自身免疫性疾病的无药物缓解的有希望的方法是自体干细胞移植（ASCT），其中通过使用免疫消融性预处理方案去除自身反应性淋巴细胞克隆，然后用自体干细胞进行拯救，其中自体反应性T细胞已经被去除，假设导致耐受自身的免疫系统的重置。已经在56名欧洲患者中进行了JIA的ASCT，超过50%的患者实现了长期的无药物缓解。该拟定方案将招募20例严重难治性全身性关节炎患者，其中10例将在美国3个移植中心之一使用统一方案（高剂量环磷酰胺、氟达拉滨和抗胸腺细胞球蛋白）接受ASCT。另外10例患者将作为第二个治疗组（治疗将在计划阶段确定）。 拟议临床试验的具体目的是：（1）确定ASCT在JIA中的安全性（两组中移植相关死亡率和严重不良事件）;（2）确定ASCT的疗效（两组中缓解率（用药和停药））;（3）确定SISR后免疫耐受发展的机制。 拟议临床试验的重要性在于，它将允许评估ASCT的安全性和有效性是否证明在更大规模的III期试验中采用这种治疗全身性关节炎的方法是合理的，并且它将提供一个难得的机会来阐明参与ASCT后耐受性发展的免疫机制，以及系统性关节炎的发病机制。

DESCRIPTION (provided by applicant): This proposal for a planning grant will enable the initiation of the proposed clinical trial, Immune Tolerance after Severe Immunosuppression with Stem Cell Rescue for JIA, which is described in the following abstract. Systemic Arthritis is a form of Juvenile Idiopathic Arthritis (JIA) which is characterized by extra-articular manifestations such as fever, rash, organomegaly and pericarditis. It is the most severe type of JIA, has the worst prognosis and is often refractory, resulting in severe joint destruction and disability as well as increased mortality. A promising method of inducing medication-free remission in refractory autoimmune disease is autologous stem cell transplantation (ASCT), in which autoreactive lymphocyte clones are removed through the use of an immunoablative conditioning regimen, followed by rescue with autologous stem cells from which the autoreactive T cells have been removed, hypothetically resulting in a re-setting of the immune system which is tolerant of self. ASCT for JIA has been performed in 56 European patients, with more than 50% achieving a long-lasting medication-free remission. This proposed protocol will enroll 20 severe refractory Systemic Arthritis patients, 10 of whom will undergo ASCT using a uniform protocol (highdose cyclophosphamide, fludarabine and anti-thymocyte globulin) at one of 3 transplanting centers in the U.S. Ten additional patients will serve as a second treatment arm (the treatment will be determined in the planning phase). The specific aims of the proposed clinical trial are to: (1) Determine the safety of ASCT in JIA (transplant related mortality and serious adverse events in the two arms); (2) Determine efficacy of ASCT (rate of remission (on and off medications) in the two arms); (3) Determine the mechanism by which immune tolerance develops following SISCR. The significance of the proposed clinical trial are that it will allow an evaluation of whether the safety and efficacy of ASCT justifies pursuing this treatment for Systemic Arthritis in larger Phase III trials, and it will provide a rare opportunity to elucidate the immune mechanisms involved in the development of tolerance after ASCT, as well as in the pathogenesis of Systemic Arthritis.