Transplantation of ESC-derived thymic epithelial progenitors expressing autoantigen(s) ameliorating experimental autoimmune encephalomyelitis

 描述（由申请人提供）：当免疫系统主动靶向并破坏自身组织时，会出现自身免疫性疾病，导致一系列临床综合征。多发性硬化症（MS）是一种中枢神经系统的自身免疫性疾病，仍然是年轻人和老年人残疾的主要原因。一般认为，MS是由针对髓鞘抗原的免疫应答介导的，随后是神经损伤，包括髓鞘的破坏和轴突损失。实验性自身免疫性脑脊髓炎（EAE）是MS最常用的动物模型，并且通过用致病性自身抗原如髓鞘少突胶质细胞糖蛋白（MOG）免疫诱导。包括MS在内的自身免疫性疾病目前无法治愈。目前治疗自身免疫性疾病的策略通常依赖于非特异性免疫抑制。尽管取得了一些成功，但免疫抑制策略难以实现长期疾病缓解，并且经常导致免疫缺陷的发展，从而导致高感染率。治疗自身免疫性疾病（包括MS）的最合乎逻辑的方式将是诱导对致病抗原的免疫耐受性，同时通过应用免疫系统用于在整个生命中维持自身耐受性的相同机制来维持全身免疫活性。为了实现这种耐受，胸腺，涉及自身耐受诱导的主要器官，必须具有足够的功能，并且自身抗原具有 持续存在于胸腺中。然而，众所周知，胸腺经历年龄依赖性退化，其功能在成人中严重受损。胸腺上皮细胞（TEC）是胸腺T细胞发育微环境的主要组成部分。TEC变性是年龄依赖性胸腺退化的主要原因。我们已经报道了小鼠胚胎干细胞（mESCs）可以在体外诱导产生胸腺上皮祖细胞（TEPs），进一步发展成功能性TECs在体内。我们还表明，在小鼠中移植表达MOG的mESC-TEPs（MOG/mTEPs）诱导MOG自身抗原特异性耐受，防止EAE发展并逆转已建立的EAE。最近，我们开发了一种有效的方案来诱导人胚胎干细胞（hESCs）分化为TEPs。在本申请中，我们提出：1）研究MOG/mTEP移植预防和治疗EAE的机制，以及2）通过移植来自MS患者的诱导多能干细胞（hiPSC）的hESC-TEP或TEP建立新的人源化EAE模型，然后确定表达MOG或其他髓鞘蛋白的这些细胞预防和治疗EAE的能力。我们提出的研究有可能导致一种新的和强大的方法来预防MS和治疗这种疾病的患者。这种方法也可用于治疗其他自身免疫性疾病时，致病的自身抗原是已知的。此外，我们的研究也将为免疫耐受和MS发病机制提供新的见解。

 DESCRIPTION (provided by applicant): Autoimmune disease arises when the immune system actively targets and destroys self-tissues, leading to a range of clinical syndromes. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and remains a major cause of disability in both young and older populations. It is generally believed that MS is mediated by immune responses against myelin antigens, followed by neurological impairment including the destruction of the myelin sheath and axonal loss. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for MS, and is induced by immunization with disease-causative self-antigens such as myelin oligodendrocyte glycoprotein (MOG). Autoimmune diseases including MS are currently incurable. Current strategies to treat autoimmune disease often rely on nonspecific immunosuppression. Despite achieving some success, immunosuppressive strategies have difficulty in achieving long-term disease relief, and often lead to the development of immune deficiency with a consequence of a high rate of infections. The most logical way to treat autoimmune diseases including MS would be to induce immune tolerance to disease-causative-antigens whilst maintaining generalized immunocompetence by applying the same mechanisms that the immune system uses to maintain self- tolerance throughout life. To achieve this tolerance, the thymus, the major organ implicated in self-tolerance induction, has to be sufficiently functional, and the self-antigen has to be persistently present in the thymus. However, it is well known that the thymus undergoes age-dependent involution, and its functions are seriously compromised in the adult. Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T cell development. TEC degeneration is the major cause of age-dependent thymic involution. We have reported that mouse embryonic stem cells (mESCs) can be induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into functional TECs in vivo. We have also shown that transplantation of mESC-TEPs expressing MOG (MOG/mTEPs) in mice induces MOG self-antigen-specific tolerance, prevents EAE development and reverses established EAE. Recently, we have developed an efficient protocol to induce the differentiation of human ESCs (hESCs) to develop into TEPs. In this application, we propose to: 1) investigate the mechanisms by which transplantation of MOG/mTEPs prevents and treat EAE, and 2) establish new humanized EAE models by transplantation of hESC-TEPs or TEPs from induced pluripotent stem cells (hiPSCs) of MS patients and then determine the ability of these cells expressing MOG or other myelin proteins to prevent and treat EAE. Our proposed studies have the potential to lead to a new and powerful approach for preventing MS and treating patients this disease. This approach could also be used in the treatment of other autoimmune diseases when the causative self-antigens are known. In addition, our studies will also provide new insights into the mechanisms for immune tolerance and MS pathogenesis.