Immune Tolerance after Severe Immunosuppression and Stem Cell Rescue for JIA

描述（由申请人提供）：

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.