Synergy between T cells and Complement in EAE

描述（由申请人提供）：我们目前对多发性硬化症（MS）免疫机制的理解大部分来自小鼠实验性自身免疫性脑脊髓炎（EAE）的研究。在模型的一种形式中，用髓鞘少突胶质细胞糖蛋白（MOG）的35-55肽免疫可诱导具有多发性硬化症多种表现的慢性进行性疾病。最近，我们发现在接种MOG 35-55后，缺乏衰变加速因子（DAF）的小鼠比野生型（WT）对照组发生更严重的EAE。DAF是一种内在的细胞表面调节剂，以前被认为只控制补体C3/C5转化酶。临床评分明显升高，淋巴细胞浸润和背柱脱髓鞘明显增加，在细胞介导的免疫试验中，CD4+ T细胞通过增殖和ifn - γ ELISPOT检测显示，MOG 35-55回忆反应强8倍。在此结果的提示下，我们在体外和体内研究了DAF对T细胞免疫反应性的诱导作用，意外地发现它通过对抗原提呈细胞（APCs）和应答细胞CD4+和CD8+细胞的作用都具有强大的抑制活性。在最近的工作中，我们发现1)MOG 35-55诱导的EAE的自身反应性扩展到蛋白脂蛋白（PLP）， 2) DAF和CD59双重缺乏的小鼠比DAF缺乏的小鼠发生更严重的疾病。一些研究表明，除了T细胞的反应性外，补体也参与了EAE的发病机制，最近的一项研究报道了CD59对全MOG蛋白诱导的疾病具有保护作用。DAF和CD59在EAE中的保护作用是通过T细胞抑制、补体抑制还是两者兼有，目前尚不清楚。然而，鉴于我们的新发现，DAF作为T细胞活化抑制剂和补体抑制剂的功能，以及CD59的潜在类似作用，原则上，工程重组DAF或CD59可能构成治疗ms的新方法。在拟议的研究中，我们将1)确定CD59缺乏对MOG 35-55和plp诱导的EAE中抗髓磷脂T细胞自身反应性和补体攻击的影响程度。2)确定DAF（如果发现CD59）发挥免疫抑制活性的细胞位点，并基于1)和2)开发适当靶向的DAF（和/或CD59）治疗剂，并测试其改善疾病的能力。

DESCRIPTION (provided by applicant): Much of our current understanding of immune mechanisms underlying multiple sclerosis (MS) comes from studies of experimental autoimmune encephalomyelitis (EAE) in mice. In 1 form of the model, immunization with the 35-55 peptide of myelin oligodendrocyte glycoprotein (MOG) induces chronic progressive disease with many manifestations of MS. Recently, we found that following MOG 35-55 immunization, mice deficient in decay accelerating factor (DAF), an intrinsic cell surface regulator previously thought to exclusively control complement C3/C5 convertases, develop dramatically more severe EAE than wild type (WT) controls. Clinical scores are markedly higher, lymphocyte infiltration and demyelination in dorsal columns are profoundly increased, and in cell-mediated immune assays, CD4+ T cells show 8-fold stronger MOG 35-55 recall responses as assessed both by proliferation and IFN-gamma ELISPOT assays. Prompted by this result, we studied DAF's effect both in vitro and in vivo on the induction of T cell immune reactivity, and unexpectedly found that it possesses potent inhibitory activity via effects both on antigen presenting cells (APCs) and responder CD4+ and CD8+ cells. In recent work we have found that 1) autoreactivity in MOG 35-55 induced EAE extends to proteolipid protein (PLP) and 2) mice doubly deficient in DAF and CD59, a related intrinsic complement inhibitor that works together with DAF, develop even more severe disease than DAF deficient mice. Some studies have shown that, in addition to T cell reactivity, complement participates in EAE pathogenesis, and a recent study has reported that CD59 protects against disease induced with whole MOG protein. Whether DAF's and CD59's protective effects in EAE are mediated via T cell inhibition, complement inhibition, or both is not established. Nevertheless, in view of our new findings of DAF's function as a T cell activation inhibitor as well as a complement inhibitor, and potentially similar effects of CD59, engineered recombinant DAF or CD59 could, in principle, constitute new therapeutic approaches for treating MS. In the proposed research we will 1) determine the extent to which deficiency of CD59 affects anti-myelin T cell autoreactivity as well as complement attack in both MOG 35-55-and PLP-induced EAE, 2) determine the cellular site(s) at which DAF (and CD59 if found) are exerting immune inhibitory activity, and, based on 1) and 2) develop appropriately targeted DAF (and/or CD59) therapeutic agents and test their abilities to ameliorate disease.