Role of B cells in host defense against Pneumocystis

B 细胞在宿主防御肺孢子虫中的作用

• 批准号: 7995500
• 负责人: Beth A Garvy
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-06 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995500
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Apoptosis; Apoptotic; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Communication; Cell Count; Cell Survival; Cell physiology; Cells; Critiques; Dendritic Cells; Disease; Drug Combinations; Generations; HIV; Host Defense; Immune response; Immunohistochemistry; Kinetics; Lung; MHC Class II Genes; Memory; Modeling; Morbidity - disease rate; Mus; Opportunistic Infections; Pathway interactions; Patients; Phase; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Population; Predisposition; Production; Published Comment; Role; Signal Transduction; Staining method; Stains; System; T-Lymphocyte; TNFRSF5 gene; Techniques; Time; Transgenic Mice; Viral Load result; annexin A5; caspase-3; cytokine; improved; in vivo; interest; lymph nodes; memory CD4 T lymphocyte; mortality; prevent; research study

DESCRIPTION (provided by applicant): Pneumocystis pneumonia is an AIDS-defining illness that has continued to cause significant morbidity and mortality among HIV-infected patients with compromised CD4 T cells. Susceptibility to Pneumocystis (PC) infection is largely due to reduced CD4 T cell number or function, however, B cells are also critical for host defense against PC. Using murine models, we have found that B-T cell interactions through costimulatory molecules such as MHC class II and CD40 on B cells have profound effects on T cell function. In the absence of B cells, CD4 T cells are not primed appropriately and fail to expand when transferred into PC-infected mice lacking T or B cells (severe combined immunodeficient, SCID mice). We hypothesize that cognate interactions in draining lymph nodes between T and B cells within the first week after PC infection provides signals for T cell expansion and CD4 T cell memory generation. Our specific aims for addressing this hypothesis are as follows: 1. To determine whether cognate or costimulatory interactions between B and T cells are required for proliferation and survival of CD4 T cells. 2. To determine whether cytokine production by B cells drives T cell survival, expansion, or memory cell generation. We will utilize established murine models of PC infection to address these three aims. These models include generation of mixed chimeric mice whose B cells are deficient in costimulatory molecules or cytokines, adoptive transfer models in which T cells are primed in the presence or absence of B cells and then transferred to SCID hosts, inducible depletion of dendritic cells using transgenic mice, and depletion of B cells using a drug combination relevant to HIV disease. In addition to determining what molecules are critically involved in T-B cell interactions, we will also perform kinetics experiments to determine when during the immune response these critical interactions take place. In addition to reduced CD4 T cell numbers, HIV-infected patients have abnormal B cell function that is related to viral load. Understanding how T and B cells must interact for efficient control of opportunistic infections is critically important for devising strategies to prevent these often times fatal opportunistic infections.

描述（由申请人提供）：肺炎藻肺炎是一种定义艾滋病的疾病，在受损的CD4 T细胞受损的HIV感染患者中继续引起明显的发病率和死亡率。对肺结压（PC）感染的敏感性很大程度上是由于CD4 T细胞的数量或功能降低，但是，B细胞对于宿主防御PC也至关重要。使用鼠模型，我们发现B-T细胞通过诸如MHC II类和B细胞的CD40等共刺激分子的B-T细胞相互作用对T细胞功能具有深远的影响。在没有B细胞的情况下，CD4 T细胞不能适当启动，并且当转移到缺乏T或B细胞的PC感染小鼠中（严重的合并免疫缺陷型SCID小鼠）。我们假设在PC感染后的第一周内，在T和B细胞之间排水淋巴结中的同源相互作用提供了T细胞扩展和CD4 T细胞存储器产生的信号。我们解决这一假设的具体目的如下：1。确定B和T细胞之间的同源性相互作用是CD4 T细胞的增殖和存活所必需的。 2。确定B细胞的细胞因子产生是否驱动T细胞存活，扩张或记忆细胞产生。我们将利用已建立的PC感染鼠模型来解决这三个目标。这些模型包括产生混合嵌合小鼠的B细胞缺乏costimulation分子或细胞因子，产物转移模型，其中T细胞在存在或不存在B细胞的情况下启动T细胞，然后转移到SCID宿主，使用Transgenic小鼠对树突状细胞的可诱导耗竭，并使用Transgenic小鼠使用BB细胞使用药物组合疾病，并使用药物组合疾病。除了确定哪些分子与T-B细胞相互作用至关重要之外，我们还将执行动力学实验，以确定在免疫反应期间何时进行这些关键相互作用。除了减少CD4 T细胞数量外，HIV感染的患者还具有与病毒载量有关的异常B细胞功能。了解T和B细胞必须如何相互作用以有效控制机会性感染对于制定策略以防止这些时间常常致命的机会感染至关重要。