Novel Hybrid Growth Factor for Immune Reconstitution in Sepsis

摘要 新型杂交生长因子在脓毒症免疫重建中的应用 脓毒症是一个主要的临床问题，死亡率超过40%，并且是导致败血症的主要原因。 在重症监护室死亡。尽管在基础和临床上投入了大量的时间和金钱， 研究包括40多个临床试验，没有FDA批准的药物用于败血症。历史上， 实验性脓毒症治疗集中在早期阶段， 免疫反应综合征（SIRS），其特征是免疫系统过度产生促炎介质， 细胞尽管靶向炎症介质（例如TNF-α或IL-1）的实验性治疗方式被广泛应用， 它们在动物模型中通常有效，但在人体临床试验中失败了。据了解，继 在急性期早期，有向代偿性抗炎反应综合征（汽车）的过渡， 限制损伤，导致免疫抑制和促进慢性感染。慢性期 脓毒症，患者在先天性和适应性免疫应答方面存在严重缺陷， 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 免疫刺激剂的使用本提案的目标是开发一种新的混合双功能 细胞因子Ha 7促进脓毒症患者的免疫重建。Ha 7是一种新的治疗方法 旨在恢复免疫细胞群体和功能，以及防止多器官衰竭。HA7 由连接到肝细胞生长因子（HGF）α链的IL-7组成。为了提高稳定性并在体内延伸 每种细胞因子与IgG分子的Fc融合，所述IgG分子被修饰以促进 异二聚体在哺乳动物细胞表达中的作用。Ha 7最初将在小鼠中测试毒性。治疗 Ha 7的功效将在脓毒症诱导的免疫接种的盲肠结扎和穿孔（CLP）模型中进行评估。 抑制小鼠。将评价用CLP和Ha 7处理的小鼠的T细胞正常数目的恢复。 淋巴细胞、树突状细胞（DC）和它们的功能，例如响应于体外免疫应答的细胞因子产生， 刺激. DC诱导同种异体应答和刺激IL-2产生的能力将在 文化Ha 7疗法恢复免疫抑制中迟发型超敏反应的能力 将在体内评价CLP后的小鼠。Ha 7将在致死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未来的工作中提交IND铺平道路。的 Ha 7独特的双重作用机制将提供一种新的潜在上级治疗选择， 目前对诊断为免疫抑制期的患者的治疗相对有限且无效， 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.