Development of a Predictive Response Signature to Anti-Thymocyte Globulin in Type 1 Diabetes

1 型糖尿病抗胸腺细胞球蛋白预测反应特征的开发

• 批准号: 10450675
• 负责人: Laura Jacobsen
• 金额: $ 12.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450675
• 关键词: Algorithms; Antithymoglobulin; Area Under Curve; Autoimmune Diseases; Beta Cell; Big Data Methods; Biological Assay; Biological Markers; C-Peptide; CD4 Positive T Lymphocytes; CSF3 gene; Career Choice; Cell Death; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Complex; Coupled; Data; Defect; Development; Development Plans; Disease; Dose; Endocrinologist; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Florida; Flow Cytometry; Frequencies; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Glycosylated hemoglobin A; Goals; Heterogeneity; Human; Immune; Immune Tolerance; Immunology procedure; Immunophenotyping; Immunotherapy; In Vitro; Individual; Institutes; Insulin-Dependent Diabetes Mellitus; Intervention; Intervention Trial; Knowledge; Manuscripts; Measures; Mediating; Methodology; Methylation; Mission; Outcome Assessment; Outcome Measure; Patient Selection; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Physicians; Placebos; Play; Preparation; Production; Regulatory T-Lymphocyte; Research Personnel; Role; Sampling; Scientist; Structure of beta Cell of islet; Subgroup; Surface; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Training; Transcript; United States National Institutes of Health; Universities; Work; adaptive immune response; arm; career; career development; clinical care; clinical efficacy; clinical trial enrollment; differential expression; epigenetic profiling; exhaust; exhaustion; immune function; immunological intervention; immunomodulatory therapies; immunotherapy clinical trials; immunotherapy trials; improved; in vitro Model; in vitro testing; in vivo; in vivo evaluation; individual patient; innovation; insulin dependent diabetes mellitus onset; methylome; next generation; peripheral blood; personalized care; personalized therapeutic; precision medicine; predicting response; predictive marker; preservation; primary outcome; prospective; response; response biomarker; responsible research conduct; side effect; single cell analysis; single-cell RNA sequencing; skills; success; transcriptome; transcriptomics; treatment optimization; treatment response

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is caused by T cell-mediated destruction of pancreatic β-cells. A combination of genetic and environmental factors contributes to this complex autoimmune disease. T1D is without any durable disease- altering therapies though several clinical trials in recent-onset T1D have demonstrated transient β-cell preservation. Anti-thymocyte globulin (ATG), which at low doses can modulate T cells and other adaptive/innate immune cells, is one such immunomodulatory therapy. Compared to placebo, ATG, given in a low dose over 2 days, demonstrated more than 40% higher preservation of C-peptide and nearly 1% lower HbA1c 2 years after therapy in recent-onset T1D subjects. However, within successful T1D immunotherapy trials like low dose ATG, there are clinical “responders” (those who produce significantly more C-peptide in response to therapy) and “nonresponders.” The field of T1D lacks an ability to determine these clinical responders prior to clinical trial enrollment and drug administration, thus exposing some individuals to ineffective interventions with considerable side effect profiles. Utilizing samples from the NIH-funded TrialNet Low-dose ATG in Recent-Onset T1D clinical trial (TN19), the objective of this proposal is to develop a response signature to ATG for use in future clinical trial enrollment criteria and eventual clinical care. The objective that transcriptome, methylome and immunophenotyping differences can identify a responder signature to ATG in T1D will be tested. Specifically, Aim 1 will develop a biomarker of response using a unique in vitro model of ATG stimulation in TN19 baseline clinical trial samples. The hypothesis being that innate and adaptive-specific genes will demonstrate differential expression and methylation profiles with distinct immune phenotypes in clinical responders compared to nonresponders following in vitro ATG stimulation. This is assessing the methodology of performing in vitro pre- enrollment testing of a subject’s peripheral blood to determine their likelihood of response. Aim 2 will identify the mechanisms of clinical efficacy through innovative single cell RNA sequencing, T cell receptor (TCR) α/β pairing, TCR immunosequencing, and surface marker expression. In addition, the function of immune subpopulations known to play a key role in immune tolerance (regulatory T cells and exhausted T cells) will add to the mechanistic determination of ATG efficacy. This work may facilitate prospective personalized therapeutic planning for individual patients or precision medicine-directed clinical trial enrollment criteria. These biomarkers would improve responder rates and reduce exposure of nonresponders to side effects. My career goal of developing predictive biomarkers for T1D immunotherapy clinical trials will be advanced by this proposal. Highly valued skills set forth in the career development plan aim to promote further independence as an investigator and include training in 1) immunological assays, 2) big data analytics, 3) responsible conduct of research, and 4) clinical trial design. The collaborative rapport and mission of training the next generation of investigators across all institutes and departments of the University of Florida provide an ideal environment for career success.

项目摘要/摘要 1型糖尿病(T1D)是由T细胞介导的胰腺β细胞破坏引起的。一种基因的组合 环境因素导致了这种复杂的自身免疫性疾病。T1D没有任何持久的疾病- 新近发病的T1D通过几项临床试验改变治疗方法证明是一过性的β细胞 保护。抗胸腺细胞球蛋白(ATG)，在低剂量下可以调节T细胞和其他适应性/先天的 免疫细胞，就是这样一种免疫调节疗法。与安慰剂相比，ATG在2%以上的低剂量给予 2年后，C肽保存率提高40%以上，糖化血红蛋白降低近1% 新近发病的T1D患者的治疗。然而，在像小剂量ATG这样的成功的T1D免疫治疗试验中， 有临床上的“反应者”(那些对治疗产生明显更多C-肽的人)和 “无动于衷的人”T1D领域缺乏在临床试验之前确定这些临床应答者的能力 登记和药物管理，从而使一些人面临相当大的无效干预 副作用简介。NIH资助的TrialNet小剂量ATG样本在新近发病的T1D临床中的应用 试验(TN19)，该建议的目标是开发对ATG的响应签名，以用于未来的临床试验 招生标准和最终的临床护理。转录组、甲基组和 免疫表型差异可以识别一个应答者对ATG的签名，在T1D将进行检测。具体来说， AIM 1将利用一种独特的体外ATG刺激模型在TN19基线上开发一种反应的生物标记物 临床试验样本。假设先天基因和适应性特异基因会表现出差异。 临床应答者不同免疫表型的表达和甲基化特征比较 体外ATG刺激后无反应者。这是评估在体外进行预实验的方法学 对受试者的外周血液进行登记测试，以确定他们的反应可能性。目标2将确定 通过创新的单细胞核糖核酸测序，T细胞受体α/β配对， TCR免疫测序和表面标志表达。此外，免疫亚群的功能 已知在免疫耐受中起关键作用(调节性T细胞和耗尽的T细胞)将增加 ATG疗效的机械性测定。这项工作可能会促进未来的个性化治疗 计划针对个别患者或精准医学指导的临床试验的入选标准。这些生物标志物 将提高应答率并减少无应答者的副作用暴露。我的职业目标是 这项提议将推动为T1D免疫治疗临床试验开发预测生物标记物。高度 职业发展计划中提出的重要技能旨在促进作为调查员的进一步独立 并包括1)免疫分析、2)大数据分析、3)负责任的研究实施方面的培训，以及 4)临床试验设计。培训下一代调查人员的合作融洽和使命 佛罗里达大学的所有学院和院系都为职业成功提供了理想的环境。