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）是一种潜在致命的自身免疫性疾病。对于弥漫性 皮肤SSc累及内脏器官，5年生存率约为50%。难治性SSc的可用疗法仍然不足，并且没有治愈性。假设如果建立了混合造血嵌合体，异基因造血细胞移植（HCT）将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。最近对SSc的高剂量免疫抑制治疗（HDIT）和自体HCT的研究显示出了希望，但并非所有患者都能耐受HDIT，复发发生，长期控制不确定。在临床前研究和临床病例报告中，同种异体HCT比自体HCT更能实现自身免疫性疾病的长期疾病控制。使用低强度预处理方案（包括氟达拉滨和全身照射）进行同种异体HCT的新方法为研究同种异体HCT的效果以及降低治疗相关死亡率的风险提供了机会。在许多临床试验中，来自HLA相同同胞供体的异基因HCT用于非恶性疾病的存活率为85-90%。对于那些发生移植物抗宿主病的患者，大多数将在3-5年后停止免疫抑制治疗。在3例SSc患者中，在同种异体HCT后观察到皮肤和疾病稳定的显著反应。在最广泛研究的患者中，随访5年，皮肤重塑，真皮纤维化几乎完全消退，微血管重建。我们建议在严重系统性硬化症患者中进行一项非清髓性预处理后异基因HCT的2期研究。终点将是安全性和疾病对同种异体细胞移植物的反应（移植物vs.自身免疫）。机制的研究提出了调查的反应，SSC相关的自身抗体，纤维化，血管病变同种异体HCT。我们还将研究微嵌合体对同种异体HCT的反应及其与临床反应的相关性。如果成功，我们将开发出一种有效的治疗系统性硬化症的方法，可以提高生活质量和生存率。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结果将有助于关注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.