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（MS）免疫机制的理解大多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肽免疫诱导具有MS的许多表现的慢性进行性疾病。最近，我们发现，在MOG 35-55免疫后，衰变加速因子（decay accelerating factor，ERF）缺陷的小鼠，ERF是一种内在细胞表面调节剂，以前被认为专门控制补体C3/C5转化酶，发生比野生型（WT）对照显著更严重的EAE。临床评分明显更高，背柱中的淋巴细胞浸润和脱髓鞘显著增加，并且在细胞介导的免疫测定中，CD 4 + T细胞显示出8倍更强的MOG 35-55回忆应答，如通过增殖和IFN-γ ELISPOT测定所评估的。基于这一结果，我们在体外和体内两方面研究了其对诱导T细胞免疫反应性的作用，并且意外地发现其通过对抗原呈递细胞（APC）和应答者CD 4+和CD 8+细胞的作用而具有有效的抑制活性。在最近的工作中，我们已经发现1）MOG 35-55诱导的EAE中的自身反应性延伸到蛋白脂质蛋白（PLP）和2）CD 59（一种与CD 59一起起作用的相关内在补体抑制剂）双重缺陷的小鼠比CD 59缺陷的小鼠发展甚至更严重的疾病。一些研究已经表明，除了T细胞反应性之外，补体参与EAE发病机制，并且最近的一项研究已经报道了CD 59针对由全MOG蛋白诱导的疾病提供保护。EAE中CD 59和CD 59的保护作用是否通过T细胞抑制、补体抑制或两者介导尚未确定。尽管如此，鉴于我们对CD 49作为T细胞活化抑制剂以及补体抑制剂的功能的新发现，以及CD 59的潜在类似作用，原则上，构成治疗MS的新治疗方法。在拟议的研究中，我们将1）确定CD 59缺陷影响抗-髓鞘T细胞自身反应性以及补体攻击在MOG 35-55-和PLP-诱导的EAE中，2）确定髓鞘T细胞自身反应性以及补体攻击在MOG 35-55-和PLP-诱导的EAE中的细胞位点，（和CD 59（如果发现））正在发挥免疫抑制活性，并且，基于1）和2）开发适当靶向的CD 59（和/或CD 59）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.