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: 6911533
• 负责人: EDWARD R SHERWOOD
• 金额: $ 26.43万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911533
• 关键词: CD1 molecule; CD95 molecule; acid base balance; animal mortality; cardiovascular function; cell mediated cytotoxicity; cell population study; cytokine; cytolysins; cytolysis; cytotoxic T lymphocyte; disease /disorder model; endopeptidases; flow cytometry; genetic susceptibility; genetically modified animals; immunogenetics; inflammation; injury; laboratory mouse; major histocompatibility complex; natural killer cells; pathologic process; peritonitis; pore forming protein; septic shock; septicemia

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）： β2微球蛋白基因敲除小鼠缺乏CD8+ T细胞和天然杀伤T细胞。与野生型小鼠相比，β2微球蛋白基因敲除小鼠在盲肠结扎和穿刺（CLP）引起的败血症期间表现出改善的生存率。通过注射抗AsiaLogM1，天然杀伤细胞的进一步消耗几乎完全抵抗了CLP诱导的死亡率。这些观察结果的机制尚不清楚。但是，两个潜在的机制具有很高的可能性。首先，CD8+ T，天然杀手T和天然杀伤细胞可以通过扩增促炎性细胞因子和趋化因子的产生来影响先天的免疫反应。这些细胞群也可能导致炎症期间直接的细胞损伤。因此，假设CD8+ T，天然杀伤和天然杀伤细胞通过扩增促炎反应和/或导致直接细胞损伤而促进或直接介导败血症诱导的死亡率。其次，β2微共菌蛋白包括I类主要组织相容性复合物和非经典抗原呈现分子CD1的β链。这两个分子对于分别表示自我和外国抗原都很重要，但是它们在调节败血症期间调节炎症反应中的作用尚不清楚。进一步假设，I类主要的组织相容性复合物，CD1和/或未识别的Beta2微球蛋白相关分子在调节败血症期间的免疫反应中起作用。该研究项目旨在检验这些假设。提出了以下特定目的：目标1：确定CD8+ T，自然杀伤和天然杀伤细胞的特定贡献，I类主要的组织相容性复合物以及CD1对致命性腹腔内脓毒症的发病机理。在对照小鼠和小鼠中，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，天然杀伤和天然杀伤细胞的功能作用，I类主要的组织相容性复合物以及CD1在调节腹腔内脓肿期间的促炎反应中。腹腔内和全身细胞因子和趋化因子的产生将在CLP之后在CD8+ T缺乏CD8+ T，天然杀伤和天然杀伤细胞的对照小鼠和小鼠中测量，这是I类主要的组织相容性复合物和CD1。特定目的3：确定胞溶液在致命的腹腔内败血症发病机理中的作用。我们将评估对照小鼠和小鼠在CD8+ T，自然杀伤剂T和CLP后自然杀伤细胞缺乏的对照小鼠和小鼠中的表现，颗粒酶，FAS和FAS的表达。穿孔/颗粒酶和FAS-FASL途径的功能作用将通过评估未缺陷型和FASL缺乏小鼠的生存，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败血性休克发病机理中很重要的新机制，其最终目的是为这种致命疾病过程开发新的治疗方法。