Autoimmune Encephalomyelitis And Regulatory T Cells

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统的炎症性疾病，仅在美国就折磨着大约40万人。对于多发性硬化症来说，理想的抗炎疗法应该是神经抗原特异性的，也就是说，它只抑制导致神经组织损伤的炎症细胞，而不是那些防止感染的炎症细胞。最近，我们对一种叫做调节性T （Treg）细胞的天然淋巴细胞亚群的理解取得了重大进展，这种细胞被免疫系统精确地用于执行抗原特异性免疫抑制。它们在维持健康方面发挥着不可或缺的作用，因为小鼠和人类缺乏它们会导致致命的炎症性疾病。它们也可能直接参与MS的发病机制，因为在几组研究的患者中，它们的功能和数量显著减少。更重要的是，包括我们在内的许多实验室已经表明，髓磷脂特异性Treg细胞的过继转移以髓磷脂特异性的方式有效地预防和改善实验性自身免疫性脑脊髓炎（MS的一种模型），而不影响对不相关抗原的免疫。这些新进展使人们认识到髓磷脂特异性Treg细胞的输注代表了ms过继细胞治疗的理想形式。然而，Treg细胞仍然是最不了解的T细胞亚群之一，因此最难用于治疗应用。这一建议的灵感来自于包括我们在内的几个实验室最近的发现，即核因子-κB家族的淋巴成员c-Rel是Treg细胞发育和功能的关键控制因子，也是人类炎症疾病的危险因子。本提案的目标是(i)确定c-Rel如何开启Foxp3基因以启动Treg细胞分化，（ii）确定Foxp3如何终止c-Rel活性以稳定Treg细胞功能，以及（iii）通过靶向c-Rel-Foxp3轴开发一种新的自身免疫性脑脊髓炎联合疗法。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts approximately 400,000 people in the United States alone. An ideal anti-inflammatory therapy for MS should be one that is neural antigen-specific, i.e., it suppresses only inflammatory cells that cause neural tissue injury but not those that protect against infections. Recently, major advances have been made in our understanding of a naturally occurring lymphocyte subset called regulatory T (Treg) cells that are used precisely by the immune system to perform antigen-specific immunosuppression. They play indispensable roles in maintaining health since their deficiency in mice and humans causes fatal inflammatory diseases. They may also be directly involved in the pathogenesis of MS since their functions and numbers are significantly reduced in patients studied by several groups. More importantly, a number of laboratories including ours have shown that adoptive transfer of myelin-specific Treg cells effectively prevents and ameliorates experimental autoimmune encephalomyelitis, a model for MS, in a myelin-specific manner, not affecting immunity against unrelated antigens. These new advances have led to the recognition that transfusion of myelin-specific Treg cells represents an ideal form of adoptive cell therapy for MS. However, Treg cells are still among the least understood T cell subsets, and consequently the most difficult to use for therapeutic applications. This proposal is inspired by recent discoveries from several laboratories including ours that c-Rel, the lymphoid member of the nuclear factor-κB family and a risk factor for human inflammatory diseases, is a key controller of Treg cell development and function. The objectives of this proposal are to (i) determine how c-Rel turns on Foxp3 gene to initiate Treg cell differentiation, (ii) determine how Foxp3 terminates c-Rel activity to stabilize Treg cell function and (iii) develop a new combination therapy for autoimmune encephalomyelitis by targeting the c-Rel-Foxp3 axis.