Alterations in CD4 T cells during sepsis

脓毒症期间 CD4 T 细胞的变化

• 批准号: 9101373
• 负责人: Thomas S Griffith
• 金额: $ 31.59万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101373
• 关键词: Acquired Immunodeficiency Syndrome; Activities of Daily Living; Acute; Affect; American; Antigenic Diversity; Back; Bacteria; CD4 Positive T Lymphocytes; Candida albicans; Cause of Death; Cecum; Cell Count; Cell physiology; Cells; Cellular Immunity; Cessation of life; Chronic; Chronic Phase; Complex; Data; Elderly; Employee Strikes; Event; Generations; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Hospitals; IL2 gene; IL7 gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunosuppression; Immunosuppressive Agents; Impairment; Incidence; Individual; Infection; Interleukin-2; Interleukin-7; Intrinsic factor; Lead; Ligation; Lymphopenia; Malignant neoplasm of prostate; Modeling; Nosocomial Infections; Opportunistic Infections; Patients; Peptide/MHC Complex; Phase; Population; Population Heterogeneity; Positioning Attribute; Predisposition; Puncture procedure; Recovery; Recovery of Function; Resolution; Sepsis; Sepsis Syndrome; Staging; Survivors; Symptoms; Syndrome; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Toxic effect; apoptosis in lymphocytes; clinically relevant; combat; commensal microbes; cytokine; cytokine therapy; experience; fitness; functional disability; high risk; improved; in vivo; innovation; malignant breast neoplasm; mortality; mouse model; novel; novel strategies; novel therapeutics; older patient; pathogen; patient population; prevent; public health relevance; reconstitution; research study; restoration; secondary infection; septic; stem; systemic toxicity

 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.

 描述（由申请人提供）：每年，脓毒症在美国医院造成的死亡人数比前列腺癌、乳腺癌和艾滋病的总和还多。老年患者是一个特别高危的群体，其发病率约占所有脓毒症病例的 60%。该患者群体非常容易受到脓毒症的影响，其死亡率比年轻患者高 100 倍，其中一些死亡发生在脓毒症后急性发作，但约 70% 的患者在初次感染后存活下来。脓毒症的慢性阶段很重要，其特征是免疫抑制，但对于协调对机会性病原体的免疫反应至关重要的脓毒症诱导的免疫抑制机制知之甚少。我们的初步数据表明，某些 Ag 特异性 CD4 T 细胞群在脓毒症急性期严重耗竭，并在整个脓毒症免疫抑制期逐渐恢复。尽管总 CD4 T 细胞数量恢复，但我们怀疑 Ag 特异性 CD4 T 细胞的长期损失会在 T 细胞库中引入“缺口”。因此，我们将研究旨在增强 CD4 T 细胞恢复和功能的新策略。在脓毒症的免疫抑制阶段，细胞因子，如 IL-2 和 IL-7，在治疗脓毒症免疫抑制方面显示出巨大的前景，但由于非特异性的全身毒性，它们可能对脓毒症患者不健康。最大限度地减少意外毒性同时最大限度地提高细胞因子疗法效力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 复合物对 CD4 T 细胞重建、库多样性的影响。脓毒症幸存者中的病原体清除尚未得到彻底研究，因此，我们的中心假设认为脓毒症引起的淋巴细胞减少会导致 Ag 特异性 CD4 的组成和/或功能发生长期变化。 T 细胞群，最终导致局部或全身继发感染背景下 CD4 T 细胞对病原体来源的 Ag 的反应减弱。以下具体目标将检验我们的假设： 目标 1) 定义脓毒症引起的内在和影响 Ag 特异性 CD4 T 细胞功能的外在因素；目标 2) 研究细胞因子复合物改善脓毒症后 CD4 T 细胞恢复和功能的能力；目标 3) 评估 CD4 T 细胞恢复的程度最终，该应用将增加我们对为什么脓毒症患者更容易继发感染的理解。随后进行二次异源感染）和肽：MHC II 四聚体方法来研究内源性 Ag 特异性 CD4 T 细胞，使我们能够完美地完成所提出的实验。