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

表达自身抗原的 ESC 来源的胸腺上皮祖细胞移植可改善实验性自身免疫性脑脊髓炎

• 批准号: 9221990
• 负责人: Laijun Lai
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221990
• 关键词: Adult; Adverse effects; Age; Animal Model; Antigen Presentation; Antigens; Architecture; Autoantigens; Autoimmune Diseases; Autologous; Cell Therapy; Cells; Clinical; Development; Disease; Embryonic Stem Cell Transplantation; Epithelial; Epithelial Cells; Experimental Autoimmune Encephalomyelitis; Generations; Germ Layers; Hematopoietic stem cells; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunization; Immunize; Immunocompetence; Immunodeficient Mouse; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Individual; Infection; Laboratories; Lead; Life; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Proteins; Myelin Sheath; Natural regeneration; Neuraxis; Neurologic; Older Population; Organ; Pathogenesis; Patients; Play; Protocols documentation; Regulatory T-Lymphocyte; Reporting; Role; Self Tolerance; Somatic Cell; Source; Syndrome; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; Time; Tissues; Transplantation; Undifferentiated; age related; autoreactive T cell; central tolerance; clinical efficacy; disability; embryonic stem cell; human embryonic stem cell; human embryonic stem cell transplantation; humanized mouse; in vivo; induced pluripotent stem cell; insight; mouse myelin oligodendrocyte glycoprotein; multiple sclerosis patient; multiple sclerosis treatment; novel; oligodendrocyte-myelin glycoprotein; peripheral tolerance; prevent; progenitor; public health relevance; reconstitution; success; thymocyte

 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.

 描述(申请人提供)：当免疫系统主动攻击和破坏自身组织，导致一系列临床症状时，就会出现自身免疫性疾病。多发性硬化症(MS)是一种中枢神经系统的自身免疫性疾病，在年轻人和老年人中仍然是导致残疾的主要原因。一般认为，MS是由抗髓鞘抗原的免疫反应介导的，其次是神经损害，包括髓鞘破坏和轴突丢失。实验性自身免疫性脑脊髓炎(EAE)是MS最常用的动物模型，由髓鞘少突胶质细胞糖蛋白(MOG)等致病自身抗原诱导而成。包括多发性硬化症在内的自身免疫性疾病目前是无法治愈的。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的疾病缓解，并经常导致免疫缺陷的发展，从而导致高感染率。治疗包括多发性硬化症在内的自身免疫性疾病最合理的方法是诱导对致病抗原的免疫耐受，同时通过应用免疫系统在一生中保持自我耐受的相同机制来保持普遍的免疫活性。为了实现这种耐受性，胸腺，这个与自我耐受性诱导有关的主要器官，必须有足够的功能，而自身抗原 持续存在于胸腺中。然而，众所周知，胸腺经历了年龄相关的退缩，其功能在成人中严重受损。胸腺上皮细胞(TECs)是胸腺T细胞发育的微环境的主要组成部分。TEC变性是年龄依赖性胸腺退行性变的主要原因。我们已经报道，小鼠胚胎干细胞(MESCs)可以在体外被诱导产生胸腺上皮祖细胞(TEPs)，在体内进一步发育成具有功能的TECs。我们还表明，将表达MOG的mESC-TEPs(MOG/mTEPs)移植到小鼠体内，可以诱导MOG自身抗原特异性耐受，防止EAE的发展，并逆转已建立的EAE。最近，我们开发了一种有效的方法来诱导人胚胎干细胞(HESCs)分化为TEPs。在这一应用中，我们建议：1)研究MOG/mTEPs移植预防和治疗EAE的机制；2)通过移植MS患者诱导的多能干细胞(HiPSCs)中的hESC-TEPs或TEPs建立新的人源化EAE模型，然后确定这些表达MOG或其他髓鞘蛋白的细胞预防和治疗EAE的能力。我们提出的研究有可能导致一种新的、强有力的方法来预防多发性硬化症和治疗这种疾病。在已知致病自身抗原的情况下，这种方法也可用于其他自身免疫性疾病的治疗。此外，我们的研究还将为免疫耐受和MS发病机制提供新的见解。