Modeling and Analysis of the Role of Microbiota Metabolites in T-Cell Differentiation

微生物群代谢物在 T 细胞分化中作用的建模和分析

• 批准号: 8888354
• 负责人: Robert Christopher Alaniz
• 金额: $ 41.37万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888354
• 关键词: Acute; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biology; CD28 gene; CD3 Antigens; Cell Therapy; Cell physiology; Cells; Chronic; Clinic; Colitis; Complex; Cytolysis; Data; Dendritic Cells; Development; Diet; Disease; Environment; Exposure to; Flow Cytometry; Gastrointestinal tract structure; Health; Homeostasis; Human; IL2RA gene; Immune Tolerance; Immunity; Immunobiology; In Vitro; Individual; Indoles; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-2; Interleukin-6; Intestines; Link; Lymphocyte; Maintenance; Mediating; Metabolic; Methods; Modeling; Molecular; Monitor; Mus; Neural Network Simulation; Outcome; Pathology; Patients; Peripheral; Phenotype; Physiological; Play; Population; Regulation; Regulatory T-Lymphocyte; Role; Safety; Signal Transduction; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Transforming Growth Factor beta; Translations; Transplantation; Tryptophan; Work; attenuation; base; bench to bedside; conditioning; cytokine; graft vs host disease; improved; in vivo; interleukin-23; microbial; protein expression; response

DESCRIPTION (provided by applicant): Regulatory T cells (Tregs) comprise a heterogeneous class of lymphocytes that are able to promote immune tolerance in peripheral tissue through cytokine secretion and modulation of dendritic cell function. Methods currently exist to selectively expand Tregs in vitro in presence of TGF-b (induced or iTregs) and transfer to patients for therapeutic inhibition of inflammation in those suffering from inflammatory bowel disease, graft- versus-host disease and other pathologies characterized by excessive inflammation. Although the adoptive transfer of iTregs has the promise to be safe in the clinic, major hurdles such as still exist in the translation of this therapeutic strategy. For example, the iTregs transferred into a patient with acute or chronic inflammation could transition from the anti inflammatory, iTreg phenotype to a pro-inflammatory, Th17 phenotype under the influence of inflammatory cytokines present in the microenvironment, and thereby, negatively contribute to the inflammatory state. Therefore, it is important to generate iTregs that possess a stable regulatory phenotype and function when introduced into an inflammatory microenvironment. Several studies link in vivo Treg development to the presence of an abundant and diverse microbial population in the intestinal tract (the microbiota). Although the microbiota's role in physiologic immune tolerance is poorly understood, a prevalent hypothesis is that the microbiota produces specific factors that promote Treg induction and modulate gut immunity towards a tolerant state. We previously demonstrated that indole, a microbiota metabolite derived from dietary tryptophan and present in the GI tract of both healthy mice and humans, attenuate indicators of inflammation. Unpublished data from our lab also show that, after conditioning in vitro in the presence of indole and iTreg-skewing conditions, CD4+ CD25- naïve T cells dramatically expand into Foxp3+ iTregs. However, iTreg stability and function can be synergistically increased or attenuated by several pro- and anti-inflammatory cytokines, and therefore, the ability to systematically predict the relationship of microbiota metabolite regulatin of Treg stability and function in inflammatory environments would contribute to our understanding of Treg immunobiology and advance Treg cell-based therapy. Our overall hypothesis is that tryptophan derived microbiota metabolites (TDMMs) induce a Treg phenotype with enhanced stability in vivo. Using Treg and Th17 data from exposure to different tryptophan derived microbiota metabolites, we propose to develop neural network models for Treg induction in vitro and stability post-transfer in vivo in the presence of indole, and use the model for generating testable predictions on optimal Treg induction, function and stability. The specific aims are: (1): To comprehensively determine the phenotype and function of TDMM-induced iTregs and Th17 cells in vitro; (2): Model the effect of TDMM on iTreg induction and Th17 attenuation in vitro and phenotype maintenance in vivo; and (3): To determine the function and stability of TDMM-induced Tregs and TDMM- attenuated Th17 cells after transfer to lymphopenic mice and mice with experimentally induced colitis.

描述（由申请人提供）：调节性T细胞（Tregs）包括一类异质性淋巴细胞，能够通过细胞因子的分泌和树突状细胞功能的调节来促进外周组织的免疫耐受。目前存在的方法是在体外TGF-b（诱导或iTregs）存在下选择性扩增treg，并转移到患有炎症性肠病、移植物抗宿主病和其他以过度炎症为特征的病理的患者中，用于治疗性抑制炎症。尽管iTregs的过继性转移在临床上是安全的，但在这种治疗策略的转化过程中仍然存在诸如此类的主要障碍。例如，转移到急性或慢性炎症患者体内的iTreg在微环境中存在的炎症细胞因子的影响下，可以从抗炎的iTreg表型转变为促炎的Th17表型，从而对炎症状态起负作用。因此，在引入炎症微环境时，产生具有稳定调节表型和功能的iTregs是很重要的。一些研究将体内Treg的发育与肠道中丰富多样的微生物种群（微生物群）的存在联系起来。尽管微生物群在生理免疫耐受中的作用尚不清楚，但一个普遍的假设是微生物群产生促进Treg诱导和调节肠道免疫耐受状态的特定因子。我们之前证明吲哚，一种来源于膳食色氨酸的微生物代谢物，存在于健康小鼠和人类的胃肠道中，可以减弱炎症指标。我们实验室未发表的数据还表明，在吲哚和itreg -skew条件下体外调节后，CD4+ CD25- naïve T细胞显着扩增为Foxp3+ itreg。然而，iTreg的稳定性和功能可以通过几种促炎性和抗炎性细胞因子协同增强或减弱，因此，系统预测炎症环境中微生物代谢物调节Treg稳定性和功能的关系将有助于我们了解Treg免疫生物学并推进Treg细胞治疗。我们的总体假设是色氨酸衍生的微生物代谢物（TDMMs）诱导Treg表型在体内具有增强的稳定性。利用暴露于不同色氨酸衍生微生物代谢物的Treg和Th17数据，我们建议建立体外诱导Treg和吲哚转移后体内稳定性的神经网络模型，并使用该模型对最佳Treg诱导、功能和稳定性进行可测试的预测。具体目的有：(1)：综合测定体外tdmm诱导的iTregs和Th17细胞的表型和功能；(2)：模拟TDMM对体外iTreg诱导和Th17衰减以及体内表型维持的影响；(3)：观察TDMM诱导的Tregs和TDMM减毒的Th17细胞转染淋巴细胞减少小鼠和实验性结肠炎小鼠后的功能和稳定性。