Novel Hybrid Growth Factor for Immune Reconstitution in Sepsis

摘要 用于脓毒症免疫重建的新型混合生长因子 脓毒症是一种主要的临床问题，死亡率超过40%，是导致 在重症监护室死亡。尽管在基础和临床方面投入了大量的时间和金钱 包括40多项临床试验在内的研究，目前还没有FDA批准的治疗败血症的药物。从历史上看， 实验性脓毒症的治疗主要集中在早期阶段，包括全身炎症 以免疫过度产生促炎介质为特征的反应综合征(SIRS) 细胞。尽管针对炎症介质(例如，肿瘤坏死因子-a或白介素1)的实验性治疗方式 它们在动物模型中通常有效，但在人类临床试验中失败了。现在可以理解的是，遵循 早期急性期，有一个过渡到代偿性抗炎反应综合征(CARS)到 限制损害，导致免疫抑制和促进慢性感染。处于慢性病阶段 脓毒症患者在先天性和获得性免疫反应方面存在严重缺陷，死亡率为 与持续性和或继发性感染有关。因此，脓毒症治疗的新范式聚焦于 关于免疫刺激剂的使用。本方案的目标是开发一种新型的双功能杂化材料 称为HA7的细胞因子可促进脓毒症患者的免疫重建。HA7是一种新的治疗方法 旨在恢复免疫细胞群和功能，并保护免受多器官衰竭的影响。HA7 由与肝细胞生长因子(HGF)链相连的IL-7组成。提高体内稳定性和延伸性 半衰期每个细胞因子与免疫球蛋白分子的Fc融合，这些分子被修饰以促进 哺乳动物细胞表达过程中的异源二聚体。HA7首先将在小鼠身上进行毒性测试。治疗性 HA7的疗效将在盲肠结扎和穿孔(CLP)脓毒症诱导免疫模型中进行评估 对小鼠的抑制作用。用CLP和HA7治疗的小鼠将被评估T细胞恢复正常的情况 淋巴细胞、树突状细胞(DC)及其功能等细胞因子的体外反应 刺激。树突状细胞诱导同种异体反应和刺激IL-2产生的能力将在 文化。HA7治疗对免疫抑制患者迟发型超敏反应的恢复作用 CLP后的小鼠将在体内进行评估。HA7将在致命的CLP模型中进行测试，以确定它是否可以 促进生存。这些研究的结果将为在今后的工作中提交IND铺平道路。这个 HA7独特的双重作用机制将提供一种新的治疗选择，可能优于 目前对诊断为免疫抑制期患者的治疗相对有限和无效 败血症。

Abstract Novel Hybrid Growth Factor for Immune Reconstitution in Sepsis Sepsis is a major clinical problem with more than a 40% mortality rate, and is the leading cause of death in intensive care units. Despite a great deal of investment of time and money in basic and clinical research including more than 40 clinical trials, there is no FDA-approved drug for sepsis. Historically, experimental sepsis treatments focused on the early phase which consists of a systemic inflammatory response syndrome (SIRS) characterized by excessive production of pro-inflammatory mediators by immune cells. Although experimental treatment modalities targeting inflammatory mediators (e.g. TNF-a or IL-1) were often effective in animal models, they failed in human clinical trials. It is now understood that following the early acute phase, there is a transition to a compensatory anti-inflammatory response syndrome (CARS) to limit damage, leading to immunosuppression and promotion of chronic infection . In the chronic phase of sepsis, patients have profound deficiencies in innate and adaptive immune responses and mortality is associated with persistent and or secondary infections. Therefore, a new paradigm of sepsis treatment focuses on the use of immunostimulating agents. The goal of this proposal is to develop a novel hybrid bifunctional cytokine called Ha7 to promote immune reconstitution in sepsis patients. Ha7 is a novel therapeutic approach designed to restore immune cell populations and function as well as protect from multiorgan failure. Ha7 consists of IL-7 linked to the a chain of hepatocyte growth factor (HGF). To improve stability and extend in vivo half-life each cytokine is fused to the Fc of IgG molecules that are modified to promote the formation of heterodimers during mammalian cell expression. Ha7 will initially be tested for toxicity in mice. The therapeutic efficacy of Ha7 will be evaluated in the cecal ligation and puncture (CLP) model of sepsis-induced immune suppression in mice. Mice treated with CLP and Ha7 will be evaluated for restoration of normal numbers of T lymphocytes, dendritic cells (DC) and their function such as cytokine production in response to in vitro stimulation. The ability of DCs to induce an allogeneic response and stimulate IL-2 production will be tested in culture. The ability of Ha7 therapy to restore the delayed type hypersensitivity response in immunosuppressed mice following CLP will be evaluated in vivo. Ha7 will be tested in a lethal CLP model to determine if it can promote survival. The results of these studies will pave the way for submission of an IND in future work. The unique dual mechanism of action of Ha7 will provide a new therapeutic option potentially superior to the relatively limited and ineffective current treatments for patients diagnosed in the immunosuppressive phase of sepsis.