Immune Reconstitution Inflammatory Syndrome in HIV-TB infected patients in Peru

秘鲁 HIV-TB 感染患者的免疫重建炎症综合征

• 批准号: 7680726
• 负责人: Arthur Clinton White
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680726
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antigens; Area; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cause of Death; Cell Count; Cells; Cellular Immunology; Cessation of life; Chronic; Complex; Defect; Depressed mood; Developed Countries; Developing Countries; Disease; Epidemiology; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; HIV; Hand; Highly Active Antiretroviral Therapy; Hospitals; Housing; IL2RA gene; IL7R gene; Immune; Immunogenetics; Immunologic Deficiency Syndromes; Immunology; In Vitro; Infection; Inflammatory; Inflammatory Response; Interleukin 2 Receptor; Interleukin 7 Receptor; Laboratories; Mediator of activation protein; Medical; Medicine; Minority; Morbidity - disease rate; Mycobacterium tuberculosis; Numbers; Patients; Peptides; Peru; Population; Production; Public Health; Relative (related person); Research Personnel; Risk; Risk Factors; Role; Site; Surface; Syndrome; T-Lymphocyte; Testing; Texas; Thinking; Time; Tuberculosis; United States; Universities; antiretroviral therapy; base; cohort; college; experience; immunoregulation; improved; microorganism antigen; reconstitution; response; restoration; transcription factor

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infects nearly 1 in 3 people in the world with over 11 million people co-infected with HIV and Mtb. TB remains the major cause of death in HIV patients worldwide. Most morbidity associated with TB in HIV patients is due to uncontrolled infection as a result of immunodeficiency. As effective anti-retroviral therapy has become available, however, new syndromes have been recognized, which are thought to result from an inflammatory response during immune reconstitution. These syndromes, termed Immune Reconstitution Inflammatory Syndrome (IRIS), develop in about 30% of active TB patients beginning effective antiretroviral therapy. The immunopathogenesis of IRIS is poorly understood, but seems to involve an overly exuberant immune/inflammatory response to microbial antigens. A subset of CD4 T cells, termed T regulatory (Treg) cells, has been recognized that are involved in modulating T cell and inflammatory responses. Tregs were initially recognized by their expression of CD4 and CD25 (the IL2 receptor alpha chain), markers also shared with activated T cells. More recently, Tregs were found to uniquely express the transcription factor Foxp3. In prior studies, we have demonstrated a complex relationship between Tregs and HIV. There was a decrease in total number of Foxp3+ Tregs in parallel to the decrease in total CD4+ cell numbers. However, the proportion of CD4 cells positive for Foxp3 was variable in advanced disease. Furthermore, IRIS develops mainly in those with low proportions of Foxp3+ cells. The broad hypothesis for this proposal is that Treg number and function are depressed in HIV-Mtb co-infected patients and that Treg defects predispose co-infected patients to chronic immune activation and IRIS, The current proposal will determine the role of Treg cells in the immunopathogenesis of IRIS by prospectively studying a cohort of HIV-TB co-infected patients beginning antiretroviral therapy. The specific aims are to test the hypothesis that HIV-TB patients who develop IRIS have a decrease of regulatory T cell proportions prior to starting antiretroviral therapy (aim1), to compare the immunogenetics of AIDS patients with tuberculosis who do and do not develop IRIS (aim 2), to test the hypothesis that IRIS in TB patients is associated with an exaggerated antigen-driven response to TB peptides (aim 3), and to TB-specific Treg function in patients with or without IRIS reconstitute a TB peptide-specific regulatory cell response (aim 4). To accomplish these goals, we have assembled a team of accomplished investigators from Texas and experienced clinician-investigators from Lima, Peru, with a large population of HIV-TB co-infected patients now beginning antiretroviral therapy. These studies should elucidate abnormalities in immunoregulation that predispose to IRIS, a problem emerging and provide a better scientific basis for optimizing antiretroviral therapy in TB endemic areas. PUBLIC HEALTH RELEVANCE Immune reconstitution inflammatory syndrome significantly complicated treatment of AIDS in areas where tuberculosis is common. This study will identify genetic and immune risk factors for this syndrome. The information will be important for improving treatment for the large number of people with both infections in developing countries, as well as in the United States.

由结核分枝杆菌 (Mtb) 引起的结核病 (TB) 感染了世界上近三分之一的人，其中超过 1100 万人同时感染 HIV 和 Mtb。结核病仍然是全世界艾滋病毒患者死亡的主要原因。 HIV 患者中与结核病相关的大多数发病是由于免疫缺陷导致的感染不受控制。然而，随着有效的抗逆转录病毒疗法的出现，人们已经认识到新的综合征，这些综合征被认为是由免疫重建过程中的炎症反应引起的。这些综合征被称为免疫重建炎症综合征 (IRIS)，约 30% 开始接受有效抗逆转录病毒治疗的活动性结核病患者会出现这些综合征。 IRIS 的免疫发病机制尚不清楚，但似乎涉及对微生物抗原过度旺盛的免疫/炎症反应。 CD4 T 细胞的一个子集，称为 T 调节 (Treg) 细胞，已被认为参与调节 T 细胞和炎症反应。 Tregs 最初是通过其 CD4 和 CD25（IL2 受体 α 链）的表达来识别的，这些标记也与激活的 T 细胞共享。最近，人们发现 Tregs 独特地表达转录因子 Foxp3。在之前的研究中，我们已经证明了 Tregs 和 HIV 之间的复杂关系。 Foxp3+ Tregs 总数的减少与 CD4+ 细胞总数的减少同时发生。然而，在晚期疾病中，Foxp3 阳性 CD4 细胞的比例是可变的。此外，IRIS 主要发生在 Foxp3+ 细胞比例较低的细胞中。该提案的广泛假设是，HIV-Mtb 合并感染患者中 Treg 数量和功能均受到抑制，并且 Treg 缺陷使合并感染患者容易出现慢性免疫激活和 IRIS。当前提案将通过前瞻性研究开始抗逆转录病毒治疗的 HIV-TB 合并感染患者队列，确定 Treg 细胞在 IRIS 免疫发病机制中的作用。具体目的是检验以下假设：发生 IRIS 的 HIV-TB 患者在开始抗逆转录病毒治疗前调节性 T 细胞比例下降（目标 1），比较发生和未发生 IRIS 的艾滋病结核病患者的免疫遗传学（目标 2），检验结核病患者中的 IRIS 与对结核肽的过度抗原驱动反应相关的假设（目标 3)，并针对患有或不患有 IRIS 的患者的结核病特异性 Treg 功能重建结核病肽特异性调节细胞反应（目标 4）。为了实现这些目标，我们组建了一支由来自德克萨斯州的资深研究人员和来自秘鲁利马的经验丰富的临床医生研究人员组成的团队，大量艾滋病毒-结核病合并感染患者现在开始接受抗逆转录病毒治疗。这些研究应阐明导致 IRIS 的免疫调节异常（这是一个正在出现的问题），并为优化结核病流行地区的抗逆转录病毒治疗提供更好的科学基础。公共卫生相关性 免疫重建炎症综合征使结核病常见地区的艾滋病治疗变得非常复杂。这项研究将确定这种综合征的遗传和免疫危险因素。这些信息对于改善发展中国家和美国大量两种感染者的治疗非常重要。