A Novel Intervention Strategy for Stroke with RTL Therapy

描述(由申请人提供)：该申请是一项第二阶段的STTR，旨在进一步研究一种新的治疗缺血性中风的干预措施。第一阶段研究了新型“设计者”疗法--重组T细胞受体配体(RTL)提供的预防缺血性中风的机制，RTL是髓鞘反应性T细胞特异性炎症功能的选择性调节剂。我们的发现表明，只有当RTL含有神经抗原肽和受体匹配的II类MHC部分时，RTL才能保护脑缺血诱导的脑损伤。我们证明了含有小鼠MHC偶联小鼠髓鞘多肽的RTL能有效地减轻小鼠的缺血性损伤(RTL551)。同样，RTL1000是一种人的MHC，与人的髓鞘多肽偶联。RTL1000在野生型小鼠中无效，但在只选择性表达人类MHC II类等位基因的人源化HLA-DR2小鼠中提供了显著的保护作用。因此，这种治疗方法代表了一种针对脑损伤特定触发的炎性免疫细胞群的新疗法。这种缺血后治疗方法很有希望，因为它专门抑制脑靶向免疫反应，同时保持免疫系统的其他部分不变。脑缺血后的炎症反应已经得到了广泛的研究，调节这种炎症反应(免疫疗法)可以改善实验模型的结果。然而，这些疗法在临床试验中并未成功应用于患者。现在支持中风是一种多器官系统疾病的观点，周围免疫系统与受伤和正在恢复的大脑之间存在相互作用。许多在最初的脑损伤中幸存下来的患者患有CIDS，中枢神经系统损伤导致的免疫抑制，导致致命的感染。因此，以减少脑缺血后的脑损伤为目标的免疫治疗必须尽量减少中枢神经系统炎症，同时不会加重CIDS。这是我们团队准备研究的一个重大障碍。我们小组利用大脑中动脉阻塞(MCAO)小鼠的缺血性中风模型，率先研究了脑缺血引起的外周免疫器官的变化。这项应用将测试三个具体的假设：1)RTL1000具有延长的治疗窗口；2)RTL1000在中老年小鼠中保持其保护潜力。3)RTL1000与组织纤溶酶原激活剂(TPA)联合应用是一种有效的治疗方法。成功完成目前的提案将决定RTL1000在治疗缺血性中风方面的疗效，以及它与tPA结合使用的能力，最终为设计试点临床试验提供路线图。在完成这项第二阶段的STTR提案后，我们将与病毒基因组学合作，继续进行中风患者的第一阶段安全性试验。

DESCRIPTION (provided by applicant): This application is a Phase II STTR to further the study of a novel therapeutic intervention for ischemic stroke. Phase I investigated the mechanism of protection against ischemic stroke provided by the novel "designer" therapy, recombinant T cell receptor ligand (RTL), a selective modulator of the inflammatory function of myelin- reactive T cell specificities. Our findings suggest that RTL protects against ischemia-induced brain injury only if the RTL contains a neuroantigen peptide and the matched Class II MHC moiety of the recipient. We demonstrate that RTL containing mouse MHC coupled to mouse myelin peptide is effective in reducing ischemic damage in mice (RTL551). Similarly, RTL1000 is a human MHC coupled to a human myelin peptide. RTL1000 is not effective in wild-type mice, but provides significant protection in 'humanized' HLA-DR2 mice that selectively express only this human MHC class II allele. As such, this treatment represents a new therapy targeting inflammatory immune cell populations specifically triggered by brain injury. This post-ischemic therapeutic approach is promising because it specifically suppresses brain targeted immune responses while leaving other portions of the immune system intact. The inflammatory response after ischemia in the brain has been studied extensively and modulation of this inflammatory response (immunotherapy) improves outcome in experimental models. However, these therapies have not translated successfully to patients in clinical trials. There is now support for the idea that stroke is a multi-organ systemic disease with interactions between the peripheral immune system and the injured and recovering brain. Many patients who survive the initial injury to the brain suffer CIDS, CNS injury-induced immunosuppression, resulting in fatal infection. Therefore, immunotherapy targeted towards minimizing brain damage following ischemia must minimize CNS inflammation while at the same time not exacerbating CIDS. This is a significant hurdle that our group is well poised to study. Our group has pioneered the study of cerebral ischemia-induced changes to peripheral immune organs using the middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke. This application will test three specific hypotheses 1) that RTL1000 has an extended therapeutic window and 2) that RTL1000 retains its protective potential in middle aged and old aged mice. Finally, 3) that RTL1000 is an effective therapy when combined with tissue plasminogen activator (tPA). Successful completion of the current proposal will determine the efficacy of RTL1000 in treatment of ischemic stroke, and its ability to be used in combination with tPA, ultimately providing a roadmap for designing pilot clinical trials. Upon completion of this Phase II STTR proposal, in partnership with Virogenomics, we will proceed to a Phase I safety trial in Stroke patients.