Uncontrolled diabetes, immune dysregulation and tuberculosis

不受控制的糖尿病、免疫失调和结核病

• 批准号: 7661731
• 负责人: BLANCA I RESTREPO
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661731
• 关键词: Accounting; Affect; Antigen-Presenting Cells; Antigens; Arts; Bacteria; Bacterial Antigens; Biological; CD80 gene; Case-Control Studies; Cell Count; Cells; Chronic; Clinic; Containment; Cytotoxic T-Lymphocytes; Defect; Development; Diabetes Mellitus; Disease; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Equation; Evaluation; Flow Cytometry; Foundations; Future; Gene Expression; Genetic Transcription; Genus Mycobacterium; Glycosylated hemoglobin A; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Harvest; High Prevalence; Human; Hyperglycemia; Immune; Immune response; Immune system; Immunity; Incubated; Infection; Inflammatory; Interferons; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-2; Interleukin-4; Interleukin-6; Kinetics; Knowledge; Laboratories; Leukocytes; Literature; Lung; Measures; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Natural Immunity; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathway interactions; Patients; Plasma; Play; Population; Predisposition; Prevention; Protein Secretion; Publishing; Pulmonary Tuberculosis; Quantitative Reverse Transcriptase PCR; Recommendation; Reporting; Rest; Risk; Role; Screening procedure; Specimen; Staging; Stimulus; T memory cell; TLR2 gene; Testing; Time; Tuberculosis; Up-Regulation; Whole Blood; base; cell type; chemokine; cytokine; design; diabetes control; human NOS2A protein; improved; killings; longitudinal analysis; mRNA Expression; macrophage; monocyte; mycobacterial; pandemic disease; perforin; prospective; public health relevance; response; tuberculosis immunity

DESCRIPTION (provided by applicant): The growing pandemic of type 2 diabetes (DM) is being increasingly recognized as a threat to tuberculosis (TB) control. Epidemiological studies consistently show DM patients are more susceptible to TB, but the underlying mechanism is unclear. We recently showed that patients with DM and TB have hyperexpression of type 1 cytokines after stimulating white blood cells with a Mycobacterium tuberculosis extract. Despite mounting this apparently protective response, TB patients with DM take longer to clear M. tuberculosis during the course of treatment than non-DM patients. The higher IFN- ? levels (and higher bacterial burden) seen in mice with established M. tuberculosis infection and chronic diabetes is thought to be the consequence of a delayed innate response. These observations led us to hypothesize that inefficient bacterial containment in humans with DM is due to dysfunctional immunity that involves either an inability to mount a timely response, and/or a less effective response resulting from a specific immune defect. To explore these possibilities we propose a prospective case-control study examining whether newly-diagnosed TB patients with poorly- controlled DM (TB-DMp) differ in the recall response to a mycobacterial antigen from those with no DM and euglycemia (TB-noDM). Whole blood from participants will be incubated with M. tuberculosis whole cell lysate, and their stimulated plasma and white blood cells will be harvested at five time points during the first 24h of this recall response. We will evaluate the dynamics of cytokine and chemokine secretion (Aim 1) and the differential mRNA expression of an extended panel of immune system components (Aim 2) in the context of three stages: i) monocyte activation and differentiation into antigen presenting cells (innate response), ii) activation of memory T lymphocytes that may express cytokines associated with protection or exacerbation of TB (adaptive response), and iii) expression of effectors by macrophages or cytotoxic T lymphocytes that ultimately kill MTB (effector response). Alterations in the timing and/or type of recall response in TB-DMp patients will be established by longitudinal analysis using generalized estimating equations. The final model will take into account possible confounders and effect modifiers. These results will further provide a list of candidate molecules with altered expression in TB-DMp patients and the basis for selection of optimal time points to study each stage of response in future studies. The long-term goal is to understand the mechanisms explaining the association between TB and DM, to develop new recommendations for improved management and prevention of TB in DM patients. Our ability to propose studies on diseases that affects millions of patients worldwide rests on our access to a population of TB patients where 36% present DM, and our state-of-the art laboratory which is close to the TB clinics. PUBLIC HEALTH RELEVANCE: As the type 2 DM pandemic accelerates, there is a growing body of literature reporting increased susceptibility of these patients to pulmonary TB. In this project we will explore whether poor diabetes control compromises the immune response to mycobacteria. This is the first step towards understanding the biological basis of the association between these two diseases, and therefore designing strategies to manage these patients more efficiently.

描述（由申请人提供）：2型糖尿病（DM）的日益流行越来越被认为是对结核病（TB）控制的威胁。流行病学研究一致表明，糖尿病患者更容易患结核病，但其潜在机制尚不清楚。我们最近发现，DM和TB患者在用结核分枝杆菌提取物刺激白色血细胞后，1型细胞因子过度表达。尽管有这种明显的保护性反应，但合并糖尿病的结核病患者需要更长的时间才能清除M。结核病在治疗过程中比非糖尿病患者。IFN-？水平（和更高的细菌负荷）的小鼠中观察到的M。结核感染和慢性糖尿病被认为是先天反应延迟的结果。这些观察结果使我们假设，DM患者的细菌控制效率低下是由于免疫功能失调，涉及无法及时响应和/或由特定免疫缺陷引起的有效性降低。为了探索这些可能性，我们提出了一个前瞻性病例对照研究，检查是否新诊断的结核病患者控制不佳的DM（TB-DMp）与那些没有DM和eukaryotic（TB-noDM）的回忆反应不同的分枝杆菌抗原。受试者的全血将与M.结核病全细胞裂解物及其刺激的血浆和白色血细胞将在该回忆应答的前24小时期间的五个时间点收获。我们将在三个阶段的背景下评估细胞因子和趋化因子分泌的动力学（目标1）以及一组扩展的免疫系统组分的差异mRNA表达（目标2）：i）单核细胞活化和分化成抗原呈递细胞ii）激活记忆T淋巴细胞，其可表达与TB的保护或恶化相关的细胞因子（适应性反应），和iii）最终杀死MTB的巨噬细胞或细胞毒性T淋巴细胞表达效应子（效应子反应）。TB-DMp患者回忆反应的时间和/或类型的改变将通过使用广义估计方程的纵向分析来确定。最终模型将考虑可能的混杂因素和效应修饰因子。这些结果将进一步提供TB-DMp患者中表达改变的候选分子列表，以及在未来研究中选择最佳时间点以研究每个反应阶段的基础。长期目标是了解结核病和糖尿病之间联系的机制，为改善糖尿病患者结核病的管理和预防提出新的建议。我们提出对影响全球数百万患者的疾病进行研究的能力取决于我们对结核病患者人群的接触，其中36%患有糖尿病，以及我们靠近结核病诊所的最先进实验室。公共卫生相关性：随着2型糖尿病大流行的加速，越来越多的文献报道这些患者对肺结核的易感性增加。在这个项目中，我们将探讨糖尿病控制不佳是否会影响对分枝杆菌的免疫反应。这是了解这两种疾病之间关联的生物学基础的第一步，因此设计策略以更有效地管理这些患者。