Resistance of Beta 2 Microglobulin Null Mice to Sepsis

Beta 2 微球蛋白无效小鼠对脓毒症的抵抗力

• 批准号: 7811704
• 负责人: EDWARD R SHERWOOD
• 金额: $ 12.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811704
• 关键词: Acid-Base Equilibrium; Acute; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Bacterial Counts; Blocking Antibodies; CD1 Antigens; CD8B1 gene; Cardiovascular Physiology; Cardiovascular system; Cell physiology; Cells; Cessation of life; Clinical; Cytolysis; Disease; Enzymes; Evaluation; Exhibits; Flow Cytometry; Functional disorder; Goals; Granzyme; Heart; IL8 gene; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interferons; Interleukin-1; Interleukin-6; Intra-abdominal; Knock-out; Knockout Mice; Ligation; Liver; Lung; Major Histocompatibility Complex; Measures; Mediating; Mediator of activation protein; Mining; Modeling; Mus; Natural Killer Cells; Organ; Pathogenesis; Pathway interactions; Peritoneal; Peritoneal Fluid; Peritonitis; Physiological; Play; Population; Probability; Process; Production; Proteins; Puncture procedure; Reading; Research; Research Design; Research Personnel; Research Project Grants; Resistance; Resources; Role; Sepsis; Septic Shock; Serum; Spleen; T-Lymphocyte; Testing; Treatment Effectiveness; beta-2 Microglobulin; cell injury; cell type; chemokine; cytokine; design; granzyme A; improved; indexing; killer T cell; mortality; perforin; porin; programs; response; septic; treatment strategy

DESCRIPTION (provided by applicant): Beta2 microglobulin knockout mice are deficient in CD8+ T cells and natural killer T cells. Compared to wild type mice, beta2 microglobulin knockout mice exhibit improved survival during sepsis caused by cecal ligation and puncture (CLP). Further depletion of natural killer cells by injection of anti-asialoGM1 confers near complete resistance to CLP-induced mortality. The mechanisms underlying these observations are unknown. However, two potential mechanisms have high probability. Firstly, CD8+ T, natural killer T and natural killer cells can impact innate immune responses by amplifying production of pro-inflammatory cytokines and chemokines. These cell populations can also cause direct cellular injury during inflammation. Therefore, it is hypothesized that CD8+ T, natural killer T and natural killer cells facilitate or directly mediate sepsis-induced mortality by amplifying the pro-inflammatory response and/or causing direct cellular injury. Secondly, beta2 microgiobulin comprises the beta chain of the class I major histocompatibility complex and the non-classical antigen-presenting molecule CD1. Both of these molecules are important for presentation of self and foreign antigens, respectively, but their roles in regulating inflammatory responses during sepsis are unknown. It is further hypothesized that the class I major histocompatibility complex, CD1 and/or unrecognized beta2 microglobulin-associated molecules play a role in modulating the immune response during sepsis. This research project is designed to test these hypotheses. The following specific aims are proposed: Aim 1: To determine the specific contributions of CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1 to the pathogenesis of lethal intra-abdominal sepsis. Mortality, bacterial counts, organ injury, cardiovascular function and acid-base balance will be measured following CLP in control mice and mice that are deficient in these cell populations and antigen-presenting molecules. Specific Aim 2: To determine the functional roles of CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1 in regulating the pro-inflammatory response during lethal intra-abdominal sepsis. Intra-abdominal and systemic cytokine and chemokine production will be measured following CLP in control mice and mice that are deficient in CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1. Specific Aim 3: To determine the role of cytolytic mechanisms in the pathogenesis of lethal intra-abdominal sepsis. We will evaluate expression of perforin, granzymes, Fas and FasL in control mice and mice that are deficient in CD8+ T, natural killer T and natural killer cells after CLP. The functional roles of the perforin/granzyme and Fas-FasL pathways will be determined by assessing survival, cardiovascular function, organ injury and acid-base balance in perforin-deficient and FasL-deficient mice. These studies are designed to define new mechanisms that are important in the pathogenesis of septic shock with the ultimate goal of developing new treatments for this lethal disease process.

描述（由申请人提供）： Beta2 微球蛋白敲除小鼠缺乏 CD8+ T 细胞和自然杀伤 T 细胞。与野生型小鼠相比，β2 微球蛋白敲除小鼠在盲肠结扎穿刺 (CLP) 引起的败血症期间表现出更高的存活率。通过注射抗asialoGM1进一步消除自然杀伤细胞，可以几乎完全抵抗CLP诱导的死亡。这些观察结果背后的机制尚不清楚。然而，两种潜在机制的可能性很高。首先，CD8+ T、自然杀伤 T 和自然杀伤细胞可以通过放大促炎细胞因子和趋化因子的产生来影响先天免疫反应。这些细胞群还可在炎症过程中引起直接细胞损伤。因此，推测 CD8+ T、自然杀伤 T 和自然杀伤细胞通过放大促炎反应和/或引起直接细胞损伤，促进或直接介导脓毒症诱导的死亡。其次，β2微球蛋白包含I类主要组织相容性复合物的β链和非经典抗原呈递分子CD1。这两种分子分别对于自身和外源抗原的呈递很重要，但它们在脓毒症期间调节炎症反应中的作用尚不清楚。进一步假设 I 类主要组织相容性复合物、CD1 和/或未识别的 β2 微球蛋白相关分子在败血症期间调节免疫反应中发挥作用。该研究项目旨在检验这些假设。提出以下具体目标： 目标 1：确定 CD8+ T、自然杀伤 T 和自然杀伤细胞、I 类主要组织相容性复合体和 CD1 对致死性腹腔内脓毒症发病机制的具体贡献。在对照小鼠和缺乏这些细胞群和抗原呈递分子的小鼠中进行 CLP 后，将测量死亡率、细菌计数、器官损伤、心血管功能和酸碱平衡。具体目标 2：确定 CD8+ T、自然杀伤 T 和自然杀伤细胞、I 类主要组织相容性复合物和 CD1 在致死性腹腔内脓毒症期间调节促炎反应中的功能作用。在对照小鼠和缺乏 CD8+ T、自然杀伤 T 和自然杀伤细胞、I 类主要组织相容性复合物和 CD1 的小鼠中进行 CLP 后，将测量腹内和全身细胞因子和趋化因子的产生。具体目标 3：确定细胞溶解机制在致死性腹内脓毒症发病机制中的作用。我们将评估 CLP 后对照小鼠和缺乏 CD8+ T、自然杀伤 T 和自然杀伤细胞的小鼠中穿孔素、颗粒酶、Fas 和 FasL 的表达。穿孔素/颗粒酶和 Fas-FasL 途径的功能作用将通过评估穿孔素缺陷和 FasL 缺陷小鼠的生存、心血管功能、器官损伤和酸碱平衡来确定。这些研究旨在定义在感染性休克发病机制中重要的新机制，最终目标是为这种致命疾病过程开发新的治疗方法。