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(申请人提供)：每年，脓毒症在美国医院导致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危的群体，其发病率约占所有败血症病例的60%。这一患者群体非常容易受到脓毒症后果的影响，死亡率是年轻患者的100倍。其中一些死亡发生在脓毒症后，但约70%的患者在最初感染后存活，并在脓毒症的慢性期死于机会性感染。脓毒症的慢性阶段很重要，以免疫抑制为特征，但对脓毒症诱导免疫抑制的机制知之甚少。CD4T细胞在脓毒症的急性期被严重耗尽，并在整个免疫抑制阶段逐渐恢复。我们的初步数据表明，尽管总的CD4T细胞数量有所恢复，但某些抗原特异性的CD4T细胞群并没有恢复。我们怀疑，抗原特异性CD4T细胞的长期丢失在T细胞谱系中引入了“间隙”。因此，我们将研究在脓毒症免疫抑制阶段加强CD4T细胞恢复和功能的新策略。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有害。在最大化细胞因子治疗效力的同时将意外毒性降至最低的一种方法是使用细胞因子：α-细胞因子单抗结合物(细胞因子复合体)。IL-2或IL-7复合体在败血症存活者的CD4T细胞重建、谱系多样性和病原体清除方面的影响尚未得到彻底的研究。因此，我们的中心假设认为，脓毒症引起的淋巴细胞减少导致抗原特异性CD4T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性继发感染的背景下，CD4T细胞对病原体来源的抗原的反应降低。以下特定的目的将检验我们的假设：目的1)确定脓毒症诱导的影响抗原特异性CD4T细胞功能的内在和外在因素；目的2)研究细胞因子复合体在脓毒症后改善CD4T细胞恢复和功能的能力；以及目的3)评估在多大程度上CD4T细胞的恢复和功能受败血症期间释放的共生细菌来源的抗原的控制。最终，这一应用将增加我们对脓毒症患者更容易发生继发感染的理解。我们结合了“两次点击”CLP脓毒症模型(CLP继发异源感染)和多肽：MHC II四聚体方法研究内源性抗原特异性CD4T细胞的经验，使我们能够完美地完成拟议的实验。