Abstract:
The development of autoimmune diseases (ADs) is thought to be caused by a dysfunction of the intrinsic ability of our immune system for \"self-nonself\" discrimination. Following the breakdown of \"self-tolerance,\" an orchestrated immune cascade develops, involving B- and T-lymphocytes and autoantibodies that target self-antigens. An imbalance of the regulatory immune network and a suitable genetic background, along with external (infectious and environmental) triggers, are all important contributors to the outbreak of clinical autoimmunity. Immunotherapies for ADs can be classified into treatments that are given continuously (chronic treatments) and therapies that are applied only once or intermittently, aiming to induce partial or complete reconstitution of the immune system [immune reconstitution therapies (IRTs)]. The principle underlying IRTs is based on the depletion of mature immune cells and the rebuilding of the immune system. During this process of immune reconstitution, a substantial change in the lymphocyte repertoire occurs, which may explain the impressive and long-term beneficial effects of IRTs, including the possibility of induction of tolerance to self-antigens. Hematopoietic (or bone marrow) stem cell transplantation (HSCT or BMT) represents the prototype-and the most radical type-of IRT therapy. The rationale for HSCT or BMT for the treatment of severe ADs is based on convincing proof in preclinical studies, utilizing various animal models of autoimmunity. More than 30 years\' worth of pioneering experiments in various models of ADs have shown that HSCT can lead to substantial improvement or even cure of the autoimmune syndromes and induction of long-term tolerance to autoantigens. The success of treatment depends on how completely the autoantigen-reactive lymphocytes and memory cells are eradicated by the conditioning chemotherapy, which is administered in a single dose before the transplantation. The most successful conditioning methods in animal models of ADs are total body irradiation (TBI) and high-dose cyclophosphamide (CY). These preclinical studies, summarized in this review, have provided important data about the therapeutic potential of HSCT in human ADs and the associated mechanisms of action and have contributed to the formulation of guidelines for clinical applications of autologous or allogeneic HSCT/BMT in refractory autoimmunity.
摘要:
自身免疫性疾病(ADs)的发展被认为是由我们的免疫系统对“自我-非自我”歧视的内在能力的功能障碍引起的。在“自我宽容”崩溃之后,“一个精心策划的免疫级联发展,涉及B和T淋巴细胞以及靶向自身抗原的自身抗体。调节免疫网络的不平衡和合适的遗传背景,以及外部(传染性和环境)触发因素,都是临床自身免疫爆发的重要因素。AD的免疫疗法可以分为连续给予的治疗(慢性治疗)和仅一次或间歇应用的治疗。旨在诱导免疫系统的部分或完全重建[免疫重建疗法(IRT)]。IRT的基本原理是基于成熟免疫细胞的消耗和免疫系统的重建。在这个免疫重建的过程中,淋巴细胞库发生了实质性变化,这可以解释IRT令人印象深刻的长期有益影响,包括诱导对自身抗原耐受的可能性。造血(或骨髓)干细胞移植(HSCT或BMT)代表了IRT治疗的原型和最激进的类型。HSCT或BMT治疗严重ADs的基本原理是基于临床前研究中令人信服的证据,利用各种自身免疫动物模型。在各种AD模型中进行的超过30年的开创性实验表明,HSCT可以导致自身免疫综合征的实质性改善甚至治愈,并诱导对自身抗原的长期耐受性。治疗的成功取决于调理化疗对自身抗原反应性淋巴细胞和记忆细胞的根除程度。移植前单剂量给药。AD动物模型中最成功的调理方法是全身照射(TBI)和高剂量环磷酰胺(CY)。这些临床前研究,在这篇综述中总结,提供了有关HSCT在人类AD中的治疗潜力以及相关作用机制的重要数据,并为在难治性自身免疫中自体或同种异体HSCT/BMT的临床应用制定了指南。