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: 10624920
• 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/10624920
• 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; Innate Immune Response; 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 Depletion; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Training; Transcript; United States National Institutes of Health; Universities; Work; adaptive immune response; alpha-beta T-Cell Receptor; 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; transcriptomic profiling; transcriptomics; treatment optimization; treatment response; trial enrollment

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.

项目总结/摘要 1型糖尿病（T1 D）是由T细胞介导的胰腺β细胞破坏引起的。基因的组合 和环境因素导致了这种复杂的自身免疫性疾病。T1 D没有任何持久的疾病- 虽然最近发生的T1 D的几项临床试验已经证明了短暂的β细胞 保存。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/先天性 免疫细胞，就是这样一种免疫调节疗法。与安慰剂相比，低剂量给予ATG超过2 两天后，C肽的保存率提高了40%以上，HbA 1c降低了近1%。 近期发作的T1 D受试者的治疗。然而，在成功的T1 D免疫治疗试验中，如低剂量ATG， 有临床“应答者”（对治疗产生显著更多C肽的人）， “无反应者”T1 D领域缺乏在临床试验前确定这些临床应答者的能力 登记和药物管理，从而使一些人暴露于无效的干预措施， 副作用简介利用来自NIH资助的TrialNet低剂量ATG的样本进行近期发作的T1 D临床研究 试验（TN 19），本提案的目的是开发对ATG的响应签名，用于未来的临床试验 入组标准和最终的临床护理。转录组、甲基化组和 将测试免疫表型差异可以识别T1 D中ATG的应答者特征。具体地说， 目标1将使用独特的ATG刺激体外模型在TN 19基线中开发反应生物标志物 临床试验样本。假设先天基因和适应特异性基因将表现出差异， 与对照组相比，临床应答者中具有不同免疫表型的表达和甲基化谱 在体外ATG刺激后无应答者。这是评估体外预处理的方法学， 受试者外周血的入组测试，以确定其响应的可能性。目标2将确定 通过创新的单细胞RNA测序，T细胞受体（TCR）α/β配对， TCR免疫测序和表面标志物表达。此外，免疫亚群的功能 已知在免疫耐受中起关键作用的T细胞（调节性T细胞和耗尽的T细胞）将增加免疫耐受性。 ATG功效的机械测定。这项工作可能有助于前瞻性的个性化治疗 针对个体患者或精准医学指导的临床试验入组标准进行规划。这些生物标志物 将提高应答率并减少无应答者对副作用的暴露。我的职业目标是 该建议将促进开发用于T1 D免疫治疗临床试验的预测生物标志物。高度 职业发展计划中列出的宝贵技能旨在促进调查员的进一步独立性 并包括以下方面的培训：1）免疫测定，2）大数据分析，3）负责任的研究行为，以及 4)临床试验设计。培养下一代调查员的协作关系和使命 在佛罗里达大学的所有研究所和部门提供了一个理想的环境，职业生涯的成功。