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.

在美国医院中，脓毒症导致的死亡人数比前列腺癌、乳腺癌和艾滋病还要多 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%。 老年人也极易受到败血症的影响，死亡率高出 100 倍 其中一些死亡是在脓毒症后急性发生的，但其中约 70% 的患者能存活下来。 初始感染，并在败血症的慢性阶段死于机会性感染。 脓毒症的发生很重要，其特点是免疫抑制，但人们对脓毒症的机制知之甚少。 脓毒症引起的免疫抑制。 CD4 T 细胞对于协调对一系列病原体的免疫反应至关重要，但已严重耗尽 在脓毒症的急性期，并在脓毒症的免疫抑制期逐渐恢复。 我们最近发表的数据显示某些 Ag 特异性 CD4 T 细胞群无法恢复， 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。 细胞在 T 细胞库中引入“间隙”，导致适应性免疫系统整体下降 在 CD4 T 细胞功能至关重要的免疫环境中，该提案将定义 CD4 T 细胞功能。 使用 CLP 模型导致 CD4 T 细胞依赖性 B 细胞反应受损的机制 随后是二次免疫或异源病原体感染。因此，我们的中心假设。 认为滤泡辅助 CD4 T (Tfh) 细胞和 B 细胞的数量和功能发生变化 亚致死性 CLP 诱导的脓毒症会抑制体液免疫并降低针对 在局部或全身继发感染的情况下遇到的病原体。 以下具体目标将检验我们的假设： 目标 1) 定义 Ag 特异性中脓毒症引起的缺陷 CD4 T 细胞和 B 细胞限制产生高效的 CD4 T 细胞依赖性 B 细胞反应； 2) 研究旨在恢复 DC 或 B 细胞数量和功能以恢复体液活力的疗法的能力 脓毒症后的免疫力；和 目标 3) 确定脓毒症对前体维持和功能的影响 最终，这一提议将加深我们对原因的理解。 脓毒症患者更容易继发感染，我们使用多种微生物脓毒症的 CLP 模型， 我们识别和研究内源性 Ag 特异性 CD4 T 细胞和 B 细胞功能的能力，以及我们的能力 测量对传染性病原体的适应性免疫反应的经验使我们处于完美的位置 定义驱动脓毒症诱导的 CD4 T 细胞依赖性 B 细胞免疫抑制的机制。