Alterations in CD4 T cells during sepsis

 描述（由申请人提供）：每年，败血症在美国医院造成的死亡人数超过前列腺癌，乳腺癌和艾滋病的总和。老年患者是一个特别高风险的群体，其发病率约占所有脓毒症病例的60%。这一患者群体非常容易受到脓毒症的影响，死亡率比年轻患者高100倍。这些死亡中的一些在脓毒症后急性发生，但这些患者中约70%在初始感染后存活，并在脓毒症的慢性阶段死于机会性感染。脓毒症的慢性阶段是重要的，其特征在于免疫抑制，但对脓毒症诱导的免疫抑制的机制知之甚少。CD 4 T细胞是协调对机会性病原体的免疫应答所必需的，在脓毒症的急性期严重耗竭，并在脓毒症的免疫抑制期逐渐恢复。我们的初步数据表明，某些Ag-特异性CD 4 T细胞群不恢复，尽管总的CD 4 T细胞的定量恢复。我们怀疑Ag特异性CD 4 T细胞的长期丧失在T细胞库内引入了“间隙”。因此，我们将研究新的策略，旨在提高CD 4 T细胞的恢复和功能，在免疫抑制阶段的脓毒症。细胞因子，如IL-2和IL-7，在脓毒症免疫抑制治疗中显示出巨大的前景，但由于非特异性全身毒性，它们可能对脓毒症患者有害。在最大化细胞因子治疗效力的同时最小化非预期毒性的一种方法是使用细胞因子：α-细胞因子mAb缀合物（细胞因子复合物）。IL-2或IL-7复合物在脓毒症幸存者中对CD 4 T细胞重建、库多样性和病原体清除的影响尚未得到彻底研究。因此，我们的中心假设认为，脓毒症诱导的淋巴细胞减少症导致Ag特异性CD 4 T细胞群的组成和/或功能的长期变化，这最终导致在局部或全身继发感染的背景下遇到的病原体来源的Ag的CD 4 T细胞应答降低。本研究的主要目的是：1）明确脓毒症后影响Ag特异性CD 4 T细胞功能的内在和外在因素; 2）探讨脓毒症后细胞因子复合物对CD 4 T细胞功能恢复的促进作用;和目的3）评估在脓毒症发作期间释放的细菌来源的Ag控制CD 4 T细胞恢复和功能的程度。最终，这一应用将增加我们对脓毒症患者更容易继发感染的原因的理解。我们结合了“两次打击”CLP脓毒症模型（CLP后继发性异源感染）和肽：MHC II四聚体方法来研究内源性Ag特异性CD 4 T细胞的经验，使我们能够完美地完成所提出的实验。

 DESCRIPTION (provided by applicant): Every year, sepsis causes more deaths in U.S. hospitals than prostate cancer, breast cancer, and AIDS combined. Elderly patients are a particularly high-risk group, with an incidence rate of ~60% of all septic cases. This patient population is very vulnerable to the consequences of sepsis, showing 100-fold higher mortality than younger patients. Some of these deaths occur acutely after sepsis, but ~70% of these patients survive the initial infection, and succumb to opportunistic infections during the chronic phase of sepsis. The chronic stage of sepsis is important and is characterized by immunosuppression, but little is known about the mechanisms of sepsis-induced immunosuppression. CD4 T cells, essential for coordinating immune responses to opportunistic pathogens, are severely depleted during the acute stage of sepsis, and gradually recover throughout the immunosuppressive phase of sepsis. Our preliminary data indicates that certain Ag-specific CD4 T cell populations do not recover, despite quantitative restoration of total CD4 T cells. We suspect that the prolonged loss of Ag-specific CD4 T cells introduces "gaps" within the T cell repertoire. Thus, we will examine novel strategies aimed at enhancing CD4 T cell recovery and function during the immunosuppressive stage of sepsis. Cytokines, such as IL-2 and IL-7, show great promise in the treatment of sepsis immunosuppression, but they can be detrimental to septic patients because of non-specific, systemic toxicity. One way to minimize unintended toxicity while maximizing potency of a cytokine therapy is to use cytokine:α-cytokine mAb conjugates (cytokine complexes). The impact of IL-2 or IL-7 complexes in terms of CD4 T cell reconstitution, repertoire diversity, and pathogen clearance in sepsis survivors has not been thoroughly studied. Accordingly, our central hypothesis holds that sepsis-induced lymphopenia results in long-lasting changes in the composition and/or function of Ag-specific CD4 T cell populations, which ultimately are responsible for the reduced CD4 T cell response to pathogen-derived Ag encountered within the context of localized or systemic secondary infections. The following specific aims will test our hypothesis: Aim 1) Define the sepsis-induced intrinsic and extrinsic factors affecting the function of Ag-specific CD4 T cells; Aim 2) Investigate the abilityof cytokine complexes to improve CD4 T cell recovery and function after sepsis; and Aim 3) Evaluate the extent to which CD4 T cell recovery and function is controlled by commensal bacteria-derived Ag released during a septic episode. Ultimately, this application will increase our understanding of why septic patients are more susceptible to secondary infections. Our combined experience with the "two-hit" CLP sepsis model (CLP followed by a secondary heterologous infection) and peptide:MHC II tetramer approaches to study endogenous Ag-specific CD4 T cells positions us perfectly to accomplish the proposed experiments.