ROLE OF B CELLS IN RESOLUTION OF P CARINII PNEUMONIA

B 细胞在解决卡氏肺结核肺炎中的作用

• 批准号: 6390656
• 负责人: Beth A Garvy
• 金额: $ 23.71万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390656
• 关键词: B lymphocyte; Pneumocystis carinii; Pneumocystis pneumonia; SCID mouse; antibody receptor; antigen presentation; cell cell interaction; cytokine; disease /disorder model; enzyme linked immunosorbent assay; gene targeting; genetically modified animals; helper T lymphocyte; histopathology; host organism interaction; laboratory mouse; leukocyte activation /transformation; lung lavage

Pneumocystis carinii (PC) pneumonia is a significant problem in immunocompromised patients, particularly those with HIV. It has been well documented that the presence of CD4+ T cells is required for resolution PC infections. In addition, it has recently been reported that mice that are deficient in B cells are susceptible to PC (4,9). This is important because AIDS patients have been shown to have B cell defects that may also render them susceptible to PC. Until recently, there have not been good animal models for studying the role of B cells in host defense to infectious diseases. Although B cell deficient mice have proven to be useful, it is not possible to determine whether susceptibility to PC in these mice is due to a lack of natural antibody, PC-specific antibody, or B cell effector functions such as antigen presentation, costimulation of T cells, or cytokine production. The goal of this proposal is to test the hypothesis that B cells play multiple roles in the resolution of PC including activating CD4+ cells through antigen presentation, producing protective antibody, and producing cytokines that lead to resolution of PC pneumonia (PCP). We will utilize existing mice that are transgenic for the B cell receptor as well as generate new murine models including 1) making mixed chimeric mice whose B cells are defective in expression of cytokines or costimulatory molecules and 2) generating new transgenic mice whose B cells express the Herpes Simplex Virus thymidine kinase gene. These new mice will have B cells that are susceptible to killing by ganciclovir. With these murine models we will address the following specific aims: 1) to determine whether B cell-T cell interactions are required for resolution of PCP; 2) to determine whether B cell-produced cytokines are required for the resolution of PC; 3) to determine whether protection against PCP is dependent on specific recognition of PC antigens by the B cells; 4) to determine whether natural antibody is required for resolution of PCP; and 5) To determine the kinetic requirements for B cell function in PC infection. Understanding host defense to PC is critical for developing vaccines or efficient therapies for preventing this potentially fatal infection.

肺炎藻（PC）肺炎是免疫功能低下的患者，尤其是HIV患者的重大问题。 有充分的文献证明，分辨率PC感染需要CD4+ T细胞的存在。 此外，最近据报道，缺乏B细胞的小鼠容易受到PC的影响（4,9）。 这很重要，因为已证明AIDS患者的B细胞缺陷也可能使他们容易受到PC的影响。 直到最近，还没有很好的动物模型来研究B细胞在宿主防御中对传染病的作用。 尽管已证明B细胞缺乏小鼠是有用的，但不可能确定这些小鼠中PC的易感性是由于缺乏天然抗体，PC特异性抗体或B细胞效应子功能，例如抗原表现，T细胞的coaltimution，T细胞或细胞因子产生。 该提案的目的是检验以下假设：B细胞在PC的分辨率中起多种作用，包括通过抗原表现激活CD4+细胞，产生保护性抗体并产生导致PC肺炎（PCP）分辨率的细胞因子。 我们将利用现有的小鼠B细胞受体转基因，并产生新的鼠模型，包括1）制造混合嵌合小鼠的B细胞在细胞因子或costimulation分子表达中有缺陷，以及2）产生新的转基因小鼠，其B细胞的B细胞表达了疱疹病毒类药物基因胺基因酶基因酶。 这些新小鼠将具有容易被Ganciclovir杀死的B细胞。 使用这些鼠模型，我们将解决以下特定目的：1）确定是否需要B细胞-T细胞相互作用才能解决PCP； 2）确定B细胞生产的细胞因子是否需要PC的分辨率； 3）确定对PCP的保护是否取决于B细胞对PC抗原的特定识别； 4）确定是否需要天然抗体才能分辨PCP； 5）确定PC感染中B细胞功能的动力学需求。 了解对PC的宿主防御对于开发疫苗或有效疗法至关重要，以防止这种潜在的致命感染。