Uncontrolled diabetes, immune dysregulation and tuberculosis

不受控制的糖尿病、免疫失调和结核病

基本信息

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
项目类别：
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

项目摘要

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）：日益流行的 2 型糖尿病 (DM) 人们越来越认识到对结核病 (TB) 控制的威胁。流行病学研究一致表明，糖尿病患者更容易感染结核病，但其潜在机制尚不清楚。我们最近发现，用结核分枝杆菌提取物刺激白细胞后，糖尿病和结核病患者的 1 型细胞因子过度表达。尽管出现了这种明显的保护性反应，但患有糖尿病的结核病患者在治疗过程中比非糖尿病患者需要更长的时间来清除结核分枝杆菌。 IFN-α越高在已确诊结核分枝杆菌感染和慢性糖尿病的小鼠中观察到的水平（和更高的细菌负荷）被认为是先天反应延迟的结果。这些观察结果使我们推测，糖尿病患者的细菌抑制效率低下是由于免疫功能失调，导致无法及时做出反应，和/或由于特定的免疫缺陷而导致反应效果较差。为了探索这些可能性，我们提出了一项前瞻性病例对照研究，检查新诊断的糖尿病控制不佳的结核病患者 (TB-DMp) 对分枝杆菌抗原的回忆反应是否与没有糖尿病和血糖正常的患者 (TB-noDM) 不同。来自参与者的全血将与结核分枝杆菌全细胞裂解物一起孵育，并且将在该召回反应的前 24 小时内的五个时间点收获他们的刺激血浆和白细胞。我们将在三个阶段中评估细胞因子和趋化因子分泌的动态（目标 1）以及一系列免疫系统成分的差异 mRNA 表达（目标 2）：i) 单核细胞活化和分化为抗原呈递细胞（先天性）反应），ii）记忆 T 淋巴细胞的激活，可能表达与结核病保护或恶化相关的细胞因子（适应性反应），以及 iii）巨噬细胞或细胞毒性 T 淋巴细胞表达效应物最终杀死MTB（效应反应）。 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果调节剂。这些结果将进一步提供在 TB-DMp 患者中表达发生改变的候选分子列表，并为选择最佳时间点以研究未来研究中每个反应阶段的基础。长期目标是了解解释结核病和糖尿病之间关联的机制，为改善糖尿病患者结核病的管理和预防制定新的建议。我们对影响全球数百万患者的疾病提出研究的能力取决于我们接触到的结核病患者群体（其中 36% 患有糖尿病）以及我们靠近结核病诊所的最先进的实验室。公共卫生相关性：随着 2 型糖尿病流行加速，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损害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，从而设计更有效地管理这些患者的策略。