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）是全球艾滋病患者死亡的主要原因。尽管在HIV-1/Mycobaterium结核病（MTB）共感染的患者中，在结核病治疗期间使用高活性的抗逆转录病毒疗法（HAART）与死亡率降低有关，但它也可能导致“矛盾反应”（PR）的生命，这两种疾病的患者在7-36％的治疗患者中发生了7-36％。 PR在最初的临床结核病改善后，在HAART启动后大约4-6周内发生。关于PR背后的起源和机制知之甚少，除了它与周围血液中结核蛋白特异性Th1反应加剧有关的CD4+ T细胞计数增加。我们的假设是在该提案中进行检验的，它是由于免疫效应子反应的不平衡重建，导致夸张的CD4+ {和CD8+} T淋巴细胞对MTB抗原的活性而产生的HIV-1/TB共同感染的机制。我们假设，由于MTB特异性T细胞的升高和/或CD4+ T细胞室内的免疫抑制调节性T细胞（Tregs）的重新基础的增加，PR+患者的这些夸张的T细胞反应在PR+患者中并非在PR-患者中出现。在这里，我们建议通过研究外周血CD4+（记忆，天真，Treg）和{CD8+（记忆，天真）} T细胞亚群及其在免疫抑制的TB/AIDS患者中的功能来检验这一假设。该试验称为Camelia（柬埔寨早期与抗逆转录病毒的晚期引入），旨在确定在联合感染的TB治疗中HAART启动的最佳时机。 {在骆驼中嵌套这些研究给我们一个独特的时间限制机会}，以（i）定义PR的免疫机制； （ii）定义了TB/HIV-1共同感染​​中T细胞功能重构的机制； 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刺激。我们还假设，我们将通过比较HAART启动之前和PR之后的反应以及PR期间通过比较PR+患者的特定抗TB抗体反应。我们预计这些研究将阐明PR的原始和机制，并将确定在HAART和TB治疗期间CD4+ {和CD8+} T细胞恢复的关键特征。我们还希望我们将确定可预测PR出现的标记和新的抗TB抗体反应。最后，我们预计这些研究将使我们对对结核和HIV-1的免疫反应的基本见解，从而对TB和AIDS共同感染进行新的治疗方法。 公共卫生相关性：结核病（TB）是艾滋病（尤其是在亚洲和非洲）的最大死亡原因，并且据估计，迄今为止，与艾滋病相关的原因有3000万人中有三分之一至一半。不幸的是，一种称为“矛盾反应”的现象使两种疾病的同时治疗变得复杂，在这种现象中，患者在药物治疗上的症状改善后，患者因进行性结核病的症状恶化。有趣的是，矛盾的反应似乎是一种免疫介导的现象，因为TB和HIV-1感染在发生治疗时都在反应治疗。因此，矛盾的反应为研究对结核病和艾滋病的夸张免疫反应提供了独特的机会，并通过这样做对两种病原体的基本免疫反应有了基本的理解。此外，该提案的另一个目标是更好地理解矛盾反应中涉及的基本免疫反应，以便我们可以更好地预测谁可能容易受到影响，并在发生时为其设计更好的治疗策略。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，旨在确定TB和AIDS共同治疗的最佳时机。