LOSS OF TH1 IMMUNE FUNCTION IN FIV INFECTED CATS

五只受感染的猫失去 TH1 免疫功能

• 批准号: 2672521
• 负责人: Mary B Tompkins
• 金额: $ 18.23万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672521
• 关键词: Retroviridae disease; Toxoplasma gondii; cats; cellular immunity; cytokine; disease /disorder model; feline immunodeficiency virus; flow cytometry; helper T lymphocyte; immunocytochemistry; in situ hybridization; leukocyte activation /transformation; polymerase chain reaction; tissue /cell culture

Infection of HIV+ individuals by organisms such as P. carinii and T. gondii has been attributed to gradual erosion of the T/H1 dependent cell mediated immune system. Most studies have focused on erosion of the "memory" immune response to these organisms, but little is known of the primary immune response to an antigen in HIV infection. As the primary response is mechanistically similar to a memory response, yet greater in magnitude, we predict that the primary response to a pathogen is a more sensitive and rapid indicator of lentivirus-induced immune deficiency. Study of the primary immune response would provide a means to analyze the cellular and molecular events leading to HIV-associated immunodeficiency in a more sensitive and rapid system than a memory response. Critical to such a study, which is not feasible in HIV, is an animal model in which specific components of the immune system can be phenotypically and functionally evaluated in response to both the immunodeficiency-inducing virus and to secondary infections. Existing data indicate that FIV infection of cats provides such a model. We have evidence that FIV causes deficiencies in the feline immune system that interfere with the ability of the cat to mount a protective primary immune response when challenged with T. gondii. We also have evidence that memory response is compromised in FIV infection. We propose to use the FIV-T. gondii co-infection model to examine the underlying immunologic defects in lentivirus infections that lead to the loss of both the primary and the memory immune responses. We will do this by studying both the generation phase (blood, lymph nodes, spleen) and the effector phase (alveolar macrophage, lung) of the immune response in cats infected with FIV-only, T. ,gondii-only, FIV followed by T. gondii, and T. gondii followed by FIV. Using bioassays for function and RT-qcPCR for mRNA, we will determine the cytokine profiles in lymphoid and lung tissue from these cats. Cytokine responses will be correlated with lymphocyte changes and alterations in virus expression in lymphoid and lung tissue using FACS analysis, immunohistochemistry, in situ hybridization, and virus infectivity assays. Comparison of the phenotype and functional profiles of these four groups of cats will help determine where in the T/H1 immune response the defect(s) occurs (APC function, clonal deletion, T/H1 to T/H2 switch). It will also determine whether the study of the primary immune response can be used as a sensitive, rapid mechanism to study HIV-induced immunodeficiency.

由卡氏肺孢子虫和T。 弓形虫病归因于T/H1依赖细胞的逐渐侵蚀 中介免疫系统。大多数研究都集中在土壤侵蚀上。 对这些有机体的“记忆”免疫反应，但对它们的 在HIV感染中对抗原的初级免疫反应。作为主要的 反应在机制上类似于记忆反应，但在 ，我们预测对病原体的主要反应是更多的 慢病毒引起的免疫缺陷的敏感和快速指标。 对初级免疫反应的研究将提供一种分析 导致HIV相关免疫缺陷的细胞和分子事件 在一个比记忆反应更敏感和更快速的系统中。至关重要的是 这种对艾滋病毒不可行的研究是一个动物模型，在这个模型中 免疫系统的特定组件可以是表型和 对免疫缺陷诱导的两种反应进行功能评估 病毒和继发性感染。现有数据表明，FIV 猫的感染提供了这样一个模型。我们有证据表明FIV导致 猫免疫系统中干扰这种能力的缺陷 当受到挑战时，猫会产生保护性的初级免疫反应 和弓形虫在一起。我们也有证据表明记忆反应受到损害 在FIV感染中。我们建议使用FIV-T。弓形虫混合感染模型 检查慢病毒感染的潜在免疫缺陷 这会导致初级免疫和免疫记忆丧失 回应。我们将通过研究两个生成阶段(血液， 淋巴结、脾)和效应相(肺泡巨噬细胞、肺) 仅感染FIV的猫的免疫反应，仅感染弓形虫的猫， FIV之后是弓形虫，弓形虫之后是FIV。使用生物测定法 对于功能和RT-qcPCR的mRNA，我们将确定细胞因子 这些猫的淋巴和肺组织的特征。细胞因子反应 将与淋巴细胞变化和病毒的变化相关 用流式细胞仪分析淋巴和肺组织中的表达， 免疫组织化学、原位杂交与病毒感染性 化验。这四种细胞的表型和功能图谱的比较 猫的群体将帮助确定T/H1免疫反应中的哪一个 出现缺陷(S)(APC功能、克隆性缺失、T/H1到T/H2切换)。 它还将决定对初级免疫反应的研究是否 可以作为一种敏感、快速的机制来研究艾滋病毒诱导的 免疫缺陷。