Nonmyeloablative Hematopoietic Cell Transplantation for Severe Systemic Sclerosis

描述(由申请人提供)： 严重系统性硬化症(SSC)是一种潜在的致命性自身免疫性疾病。对于弥漫性疾病患者 皮肤SSc伴内脏受累，5年存活率约为50%。现有的治疗难治性SSc的方法仍然不足，而且没有一种是治愈的。假设异基因造血细胞移植(HCT)通过消除自身反应性宿主免疫效应细胞或调节残留宿主免疫效应细胞的活性而导致持续缓解，如果建立了混合造血嵌合体。最近对大剂量免疫抑制疗法(HDIT)和自体HCT治疗SSC的研究显示出希望，但并不是所有的患者都能耐受HDIT，复发已经发生，而且长期控制尚不确定。在临床前研究和临床病例报告中，自身免疫性疾病的长期疾病控制使用同种异体血细胞移植比自体血细胞移植更好。采用低强度预适应方案(包括氟达拉滨和全身照射)进行同种异体HCT的新方法为研究降低治疗相关死亡风险的同种异体HCT的效果提供了机会。目前，在许多临床试验中，非恶性疾病的HLA相合同胞供者的异基因血细胞移植的存活率为85-90%。对于那些发生移植物抗宿主病的患者，大多数人会在3-5年后停止免疫抑制治疗。同种异体HCT后3例SSc患者的皮肤和疾病稳定有了显著的反应。在最广泛研究的患者中，随访5年，皮肤重塑，皮肤纤维化几乎完全消失，微血管重建。我们建议对严重系统性硬化症患者进行非清髓性预适应后异基因红细胞移植的2期研究。终点将是疾病对同种异体细胞移植物的安全性和反应(移植物与自身免疫)。建议进行机制研究，以调查SSC相关自身抗体、纤维化和血管病变对同种异体HCT的反应。我们还将调查微嵌合体对异基因HCT的反应及其与临床反应的关系。如果成功，我们将开发出一种有效的系统性硬化症治疗方法，可以提高生活质量和存活率。这项研究中关于诱导SSC持续缓解后器官反应和恢复的独特观察将有助于集中和指导其他非移植研究活动。

DESCRIPTION (provided by applicant): Severe systemic sclerosis (SSc) is a potentially fatal autoimmune disease. For patients with diffuse cutaneous SSc with internal organ involvement, 5-year survival is approximately 50%. Available therapies for refractory SSc remain inadequate and none are curative. It is hypothesized that allogeneic hematopoietic cell transplantation (HCT) will result in a sustained remission by the elimination of the autoreactive host immune effector cells or modulation of the activity of residual host immune effector cells if mixed hematopoietic chimerism is established. Recent studies of high-dose immunosuppressive therapy (HDIT) and autologous HCT for SSc have shown promise, but not all patients will tolerate HDIT, relapses have occurred, and long-term control is uncertain. In preclinical studies and clinical case reports, long-term disease control of autoimmune disease was better achieved with allogeneic than with autologous HCT. New methods of performing allogeneic HCT with low-intensity conditioning regimens which include fludarabine and total body irradiation offer the opportunity to investigate the effect of allogeneic HCT with reduced risk of treatment-related mortality. Survival of 85-90% is being reported now in many clinical trials of allogeneic HCT from HLA-identical sibling donors for nonmalignant diseases. For those patients who develop graft-versus-host disease, most will discontinue immunosuppressive therapy after 3-5 years. A significant response in the skin and disease stabilization has been observed in 3 patients with SSc after allogeneic HCT. In the most extensively studied patient followed for 5 years, there was skin remodeling with almost complete resolution of the dermal fibrosis and re-establishment of the microvasculature. We propose to conduct a phase 2 study of allogeneic HCT after nonmyeloablative conditioning in patients with severe systemic sclerosis. End points will be safety and response of the disease to the allogeneic cell graft (graft vs. autoimmunity). Mechanistic studies are proposed to investigate the response of the SSc-related autoantibodies, fibrosis, and vasculopathy to allogeneic HCT. We will also investigate the response of microchimerism to allogeneic HCT and the association to clinical response. If successful, we will have developed an effective therapy of systemic sclerosis which can improve quality of life and survival. The unique observations in this study regarding responses and recovery of organs after inducing a sustained remission of SSc will serve to focus and direct other non-transplant research activities.