Impairment and recovery of CD4 T cell-dependent B cell responses after sepsis

脓毒症后 CD4 T 细胞依赖性 B 细胞反应的受损和恢复

• 批准号: 10084212
• 负责人: Thomas S Griffith
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084212
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adaptive Immune System; Affect; Aging; American; Antibody Formation; Automobile Driving; Award; B-Lymphocytes; Back; Bacterial Infections; CD4 Positive T Lymphocytes; Cause of Death; Cell Count; Cell physiology; Cells; Cessation of life; Chronic; Chronic Phase; Data; Defect; Dendritic Cells; Diagnostic Procedure; Elderly; Event; Functional disorder; Generations; Goals; Gold; Healthcare Systems; Hospitals; Human; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immunity; Immunization; Immunologics; Immunosuppression; Immunosuppressive Agents; Impairment; Incidence; Infection; Intra-abdominal; Investigation; Lead; Lymphopenia; Maintenance; Malignant neoplasm of prostate; Measures; Microbe; Modeling; Multi-Drug Resistance; Nosocomial Infections; Opportunistic Infections; Paper; Patients; Peritonitis; Phase; Population; Positioning Attribute; Predisposition; Publications; Publishing; Quality of life; Recovery; Secondary Immunization; Secondary to; Sepsis; Standard Model; Supporting Cell; Survivors; T-Lymphocyte; Testing; Therapeutic; Therapeutic procedure; Toxin; adaptive immune response; adaptive immunity; base; cecal ligation puncture; combat; experience; extracellular; high risk population; immune system function; innovation; malignant breast neoplasm; memory CD4 T lymphocyte; microbial; mortality; mouse model; novel therapeutics; older patient; pathogen; polymicrobial sepsis; prevent; response; restoration; secondary infection; septic; septic patients; socioeconomics; therapy design

Sepsis causes more deaths in U.S. hospitals annually 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. The elderly are also extremely 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 a range of pathogens, are severely depleted during the acute stage of sepsis, and gradually recover throughout the immunosuppressive phase of sepsis. Our recent publication included data showing 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 leading to overall decreased adaptive immune system function. Among the immunological settings where CD4 T cell function is vital, this proposal will define the mechanisms responsible for the impairment of CD4 T cell-dependent B cell responses using the CLP model followed by secondary immunization or heterologous pathogen infection. Accordingly, our central hypothesis holds that alterations in the number and function of both follicular helper CD4 T (Tfh) cells and B cells after sublethal CLP-induced sepsis is responsible for suppressed humoral immunity and reduced protection against pathogens encountered within the context of localized or systemic secondary infections. The following specific aims will test our hypothesis: Aim 1) Define the sepsis-induced defects in Ag-specific CD4 T cells and B cells that restrict the generation of a productive CD4 T cell-dependent B cell response; Aim 2) Investigate the ability of therapies designed to restore DC or B cell number and function to revitalize humoral immunity after sepsis; and Aim 3) Determine the impact of sepsis on the maintenance and function of pre- existing memory CD4 T cells and B cells. Ultimately, this proposal will increase our understanding of why septic patients are more susceptible to secondary infections. Our use of the CLP model of polymicrobial sepsis, our ability to identify and study the function of endogenous Ag-specific CD4 T cells and B cells, and our experience measuring the adaptive immune response to infectious pathogens put us in the perfect position to define the mechanism(s) driving sepsis-induced suppression of CD4 T cell-dependent B cell immunity.

脓毒症每年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 加在一起。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%。 老年人也极易受到败血症的影响，死亡率高出100倍。 而不是年轻的病人。其中一些死亡发生在脓毒症后，但其中约70%的患者存活了下来 初始感染，并在败血症的慢性期死于机会性感染。慢性期 脓毒症的发病机制很重要，其特点是免疫抑制，但对其发病机制知之甚少。 脓毒症引起的免疫抑制。 对于协调对一系列病原体的免疫反应至关重要的CD4T细胞严重枯竭 在脓毒症的急性期，并在整个败血症的免疫抑制阶段逐渐恢复。 我们最近发表的数据显示，某些抗原特异性的CD4T细胞群不会恢复， 尽管总的CD4T细胞数量有所恢复。我们怀疑，抗原特异性CD4T细胞的长期丢失 细胞在T细胞谱系中引入“间隙”，导致适应性免疫系统整体下降 功能。在CD4T细胞功能至关重要的免疫学环境中，这项提议将定义 用CLP模型研究CD4T细胞依赖的B细胞反应受损的机制 其次是二次免疫或异源病原体感染。因此，我们的中心假设 认为术后滤泡辅助性T细胞(TFH)和B细胞数量和功能的变化 亚致死性CLP诱导的脓毒症导致体液免疫抑制和对 在局部或系统性继发感染的背景下遇到的病原体。 以下具体目的将检验我们的假设：目的1)确定脓毒症引起的Ag特异性缺陷 CD4T细胞和B细胞，限制产生生产性的CD4T细胞依赖的B细胞反应；目的 2)研究旨在恢复DC或B细胞数量和功能以恢复体液功能的疗法的能力 目的3)确定脓毒症对Pre-Pre的维持和功能的影响。 存有记忆的CD4T细胞和B细胞。最终，这项提议将增加我们对原因的理解 败血症患者更容易发生继发感染。我们使用了CLP的多菌败血症模型， 我们识别和研究内源性抗原特异性CD4T细胞和B细胞功能的能力，以及我们的 测量对感染病原体的适应性免疫反应的经验使我们处于完美的位置 明确脓毒症诱导抑制CD4T细胞依赖的B细胞免疫的机制(S)。