A Novel Intervention Strategy for Stroke with RTL Therapy

描述（由申请人提供）：该申请是一项II期STTR，旨在进一步研究一种新的缺血性卒中治疗干预措施。I期研究了新型“设计”疗法——重组T细胞受体配体（RTL）对缺血性卒中的保护机制，RTL是髓磷脂反应性T细胞特异性炎症功能的选择性调节剂。我们的研究结果表明，只有当RTL含有神经抗原肽和受体匹配的II类MHC片段时，RTL才能防止缺血诱导的脑损伤。我们证明含有小鼠MHC与小鼠髓磷脂肽偶联的RTL可有效减轻小鼠的缺血性损伤（RTL551）。类似地，RTL1000是与人髓磷脂肽偶联的人MHC。RTL1000在野生型小鼠中无效，但在选择性表达这种人类MHC II类等位基因的“人源化”HLA-DR2小鼠中提供显著的保护。因此，这种治疗方法代表了一种针对脑损伤特异性触发的炎症免疫细胞群的新疗法。这种缺血后的治疗方法很有希望，因为它可以特异性地抑制大脑靶向免疫反应，同时使免疫系统的其他部分保持完整。脑缺血后的炎症反应已被广泛研究，这种炎症反应的调节（免疫治疗）改善了实验模型的结果。然而，这些疗法并没有成功地转化为临床试验中的患者。现在有证据支持中风是一种多器官全身性疾病，与周围免疫系统和受伤和恢复的大脑之间存在相互作用。许多在最初脑损伤后存活下来的患者会遭受CIDS，中枢神经系统损伤引起的免疫抑制，导致致命的感染。因此，旨在减少缺血后脑损伤的免疫治疗必须减少中枢神经系统炎症，同时不加剧CIDS。这是我们小组准备研究的一个重大障碍。本课组率先利用脑中动脉闭塞（MCAO）小鼠缺血性脑卒中模型研究脑缺血诱导的外周免疫器官变化。该应用将测试三个特定假设：1)RTL1000具有延长的治疗窗口；2)RTL1000在中老年小鼠中保留其保护潜力。最后，3)RTL1000与组织型纤溶酶原激活剂（tPA）联合治疗是有效的。当前提案的成功完成将确定RTL1000治疗缺血性卒中的疗效，以及其与tPA联合使用的能力，最终为设计中试临床试验提供路线图。在完成这项II期STTR提案后，我们将与Virogenomics合作进行卒中患者的I期安全性试验。

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. PUBLIC HEALTH RELEVANCE: Stroke is one of the leading causes of death and the leading cause of disability in the United States. Unfortunately, there is currently only a single drug available to improve outcome following ischemic stroke, tissue plasminogen activator (tPA), with a limited therapeutic window of >4.5 hrs. The proposed studies will demonstrate the efficacy of RTL1000 in treatment of ischemic stroke, and its ability to be used in combination with tPA.