T CELL SUBSETS AND THEIR FUNCTION IN TB/HIV PARADOXICAL REACTIONS

T 细胞亚群及其在 TB/HIV 矛盾反应中的功能

• 批准号: 7554709
• 负责人: ANNE GOLDFELD
• 金额: $ 36.75万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554709
• 关键词: Acquired Immunodeficiency Syndrome; Africa; Antibody Formation; Antigens; Antitubercular Agents; Asia; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cambodia; Cause of Death; Cell Count; Cell physiology; Clinical; Clinical Trials; Clinical Trials Design; Development; Disease; Enzyme-Linked Immunosorbent Assay; Goals; HIV; HIV Antigens; HIV-1; Highly Active Antiretroviral Therapy; Immune; Immune response; Immunosuppressive Agents; In Vitro; Individual; Infection; Inflammatory; Laboratory Markers; Lead; Life; Mediating; Memory; Methods; Mycobacterium tuberculosis; Patients; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Phase; Phenotype; Plasma; Production; Protocols documentation; Reaction; Risk; Role; Staining method; Stains; Stimulus; Symptoms; Syndrome; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tuberculin; Tuberculosis; United States National Institutes of Health; Viral Load result; acronyms; antiretroviral therapy; base; cytokine; design; immunosuppressed; improved; insight; memory CD4 T lymphocyte; mortality; novel marker; novel therapeutic intervention; pathogen; peripheral blood; public health relevance; reconstitution; research study; response; restoration; treatment strategy; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis (TB) is the leading cause of death in AIDS patients worldwide. Although the use of highly active antiretroviral therapy (HAART) during TB treatment in HIV-1/Mycobaterium tuberculosis (MTb) co-infected patients is associated with reduced mortality, it can also result in life threatening "paradoxical reactions" (PR), which occur in 7-36% of co-infected patients treated for both diseases. PR occurs after initial clinical TB improvement and within approximately 4-6 weeks after HAART initiation. Very little is known about the origin and mechanisms behind PR, except that it is associated with increased CD4+ T cell counts and the exacerbation of tuberculin-specific Th1 responses in peripheral blood. Our hypothesis, to be tested in this proposal, is that the mechanism underlying PR in HIV-1/TB co-infection occurs due to an unbalanced reconstitution of immune effector responses resulting in exaggerated CD4+ {and CD8+}T lymphocyte activities to MTb antigens. We hypothesize that these exaggerated T cell responses develop in PR+ patients, but not in PR- patients, due to a more robust rise of MTb-specific T cells and/or decreased reconstitution of immunosuppressive regulatory T cells (Tregs) within the CD4+ T cell compartment. Here, we propose to test this hypothesis by investigating peripheral blood CD4+ (memory, naive, Tregs) and {CD8+ (memory, naive)} T cell subsets and their function in immunosuppressed TB/AIDS patients on dual therapy from an ongoing clinical trial in Cambodia. This trial, called CAMELIA (CAMbodian Early vs. Late Introduction of Antiretrovirals), is designed to determine the optimal timing of HAART initiation in co-infected AIDS patients on TB therapy. {Nesting these studies in the CAMELIA gives us a unique time-limited opportunity} to (i) define the immunological mechanisms underlying PR; (ii) define the mechanisms of reconstitution of T cell functions in TB/HIV-1 co-infection; and (iii) to associate these T cell responses with clinical and laboratory markers found in PR patients in the CAMELIA trial.} To accomplish these goals, we will prospectively analyze CD4+ and CD8+ T cell subsets and their proliferative capacity and cytokine responses using several methods, including intracellular cytokine staining (ICS), proliferation analysis and ELISA, in response to a number of MTb and HIV- 1-specific stimuli. We also hypothesize that we will identify specific anti-TB antibody responses in PR+ patients by comparing responses prior to and after HAART initiation, as well as during PR. We anticipate that these studies will elucidate the origin and mechanisms underlying PR, and will identify key features of CD4+ {and CD8+ } T cell restoration during HAART and TB therapy. We also expect that we will identify markers and new anti-TB antibody responses that are predictive of the emergence of PR. Finally, we anticipate that these studies will give us fundamental insights into the immune response to TB and HIV-1 and, thus, to new therapeutic approaches to TB and AIDS co-infection. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is the largest cause of death in the setting of AIDS, particularly in Asia and Africa, and has claimed an estimated one third to one half of the 30 million people who have from AIDS-related causes to date. Unfortunately, simultaneous treatment of the two diseases is complicated by a phenomenon known as the `paradoxical reaction' where the patient deteriorates with symptoms of progressive TB after symptoms had improved on drug therapy. Intriguingly, the paradoxical reaction appears to be an immune-mediated phenomenon since both the TB and HIV-1 infections are responding to therapy when it occurs. Thus, the paradoxical reaction provides a unique opportunity to study exaggerated immune responses to TB and AIDS and, by doing so, to gain a fundamental understanding into the basic immune response to both pathogens. In addition, another goal of this proposal is to better understand the basic immune response involved in the paradoxical reaction so that we may be better able to predict who may be susceptible to it, as well as devise better treatment strategies for when it occurs. We will conduct these studies in the context of an ongoing clinical trial designed to determine the optimal timing of TB and AIDS co-therapy in Cambodia.

描述（由申请人提供）：结核病（TB）是全世界艾滋病患者死亡的主要原因。尽管在 HIV-1/结核分枝杆菌 (MTb) 合并感染患者的结核病治疗期间使用高效抗逆转录病毒疗法 (HAART) 可降低死亡率，但它也可能导致危及生命的“矛盾反应”(PR)，这种情况发生在接受这两种疾病治疗的合并感染患者中的 7-36%。 PR 发生在初次临床结核病改善后以及开始 HAART 后约 4-6 周内。我们对 PR 背后的起源和机制知之甚少，只知道 PR 与 CD4+ T 细胞计数增加和外周血中结核菌素特异性 Th1 反应加剧有关。我们的假设（将在本提案中进行检验）是，HIV-1/TB 合并感染中 PR 的机制是由于免疫效应器反应的不平衡重建导致 CD4+{和 CD8+}T 淋巴细胞对 MTb 抗原的活性过度所致。我们假设这些过度的 T 细胞反应在 PR+ 患者中出现，但在 PR- 患者中则不然，因为 MTb 特异性 T 细胞的增加更加强劲和/或 CD4+ T 细胞区室内免疫抑制性调节性 T 细胞 (Treg) 的重建减少。在这里，我们建议通过在柬埔寨正在进行的一项临床试验中研究接受双重治疗的免疫抑制结核病/艾滋病患者的外周血 CD4+（记忆，幼稚，Treg）和 {CD8+（记忆，幼稚）} T 细胞亚群及其功能来检验这一假设。这项名为 CAMELIA（柬埔寨早期与晚期引入抗逆转录病毒药物）的试验旨在确定接受结核病治疗的合并感染艾滋病患者开始 HAART 的最佳时机。 {将这些研究嵌套在 CAMELIA 中为我们提供了一个独特的限时机会}：(i) 定义 PR 背后的免疫机制； (ii) 确定 TB/HIV-1 合并感染中 T 细胞功能重建的机制； (iii) 将这些 T 细胞反应与 CAMELIA 试验中 PR 患者中发现的临床和实验室标志物联系起来。}为了实现这些目标，我们将使用多种方法，包括细胞内细胞因子染色 (ICS)、增殖分析和 ELISA，前瞻性地分析 CD4+ 和 CD8+ T 细胞亚群及其增殖能力和细胞因子反应，以响应一些 MTb 和 HIV-1 特异性 刺激。我们还假设，我们将通过比较 HAART 开始之前和之后以及 PR 期间的反应来确定 PR+ 患者中的特异性抗结核抗体反应。我们预计这些研究将阐明 PR 的起源和机制，并将确定 HAART 和结核病治疗期间 CD4+ {和 CD8+ } T 细胞恢复的关键特征。我们还期望能够识别出可预测 PR 出现的标志物和新的抗结核抗体反应。最后，我们预计这些研究将为我们提供关于结核病和 HIV-1 免疫反应的基本见解，从而为结核病和艾滋病合并感染提供新的治疗方法。 公共卫生相关性：结核病 (TB) 是艾滋病造成的最大死亡原因，特别是在亚洲和非洲，迄今为止，估计有 3000 万艾滋病相关患者中的三分之一到二分之一死于结核病。不幸的是，两种疾病的同时治疗因一种被称为“矛盾反应”的现象而变得复杂，即在药物治疗症状改善后，患者的病情恶化，并出现进行性结核病的症状。有趣的是，这种矛盾的反应似乎是一种免疫介导的现象，因为结核病和 HIV-1 感染在发生时都会对治疗产生反应。因此，这种矛盾的反应提供了一个独特的机会来研究对结核病和艾滋病的过度免疫反应，并通过这样做，获得对这两种病原体的基本免疫反应的基本了解。此外，该提案的另一个目标是更好地了解矛盾反应所涉及的基本免疫反应，以便我们能够更好地预测谁可能对其敏感，并在其发生时制定更好的治疗策略。我们将在一项正在进行的临床试验的背景下进行这些研究，该试验旨在确定柬埔寨结核病和艾滋病联合治疗的最佳时机。