Plasma-induced signatures as a measure disease heterogeneity and immunomodulation in T1D clinical trials

血浆诱导特征作为 T1D 临床试验中疾病异质性和免疫调节的衡量标准

• 批准号: 10320064
• 负责人: Martin J Hessner
• 金额: $ 52.74万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320064
• 关键词: Antigens; Area Under Curve; Attention; Autoantibodies; Beta Cell; Biological Assay; C-Peptide; CD4 Positive T Lymphocytes; CSF3 gene; CTLA4-Ig; Cell physiology; Childhood; Clinical; Clinical Trials; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Enrollment; Exhibits; Failure; Family; Fostering; Frequencies; Future; Genetic Transcription; Haplotypes; Heterogeneity; Immune; Immunologics; Immunotherapy; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-1; Interleukin-10; Interleukins; Intervention Trial; Knowledge; Lesion; Measures; Mediating; Modeling; Molecular; Monitor; Newly Diagnosed; Outcome; Partial Remission; Participant; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Placebos; Plasma; Population; Rattus; Regulatory T-Lymphocyte; Reporting; Rodent Model; Sampling; Serum; Siblings; Stains; Structure of beta Cell of islet; Subgroup; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transforming Growth Factor beta; Virus Diseases; age related; aluminum sulfate; antagonist; anti-CD20; autoreactivity; base; clinical remission; cohort; diabetes pathogenesis; disease heterogeneity; experience; extracellular; high risk; immunological intervention; immunomodulatory strategy; immunoregulation; improved; insight; insulin dependent diabetes mellitus onset; islet; neutrophil; patient response; patient stratification; personalized medicine; proband; receptor; response; sample archive; stem; success; treatment response

PROJECT SUMMARY/ABSTRACT A better understanding of Type 1 diabetes (T1D) pathogenesis has enabled development of immunomodulatory strategies aimed at inducing clinical remission. While much has been learned, the positive effects observed in these trials have generally been of limited duration and patient responses have been mixed. It has been suggested that this outcome has stemmed from an incomplete understanding of the complexity and heterogeneity of T1D pathogenesis. New measures of immune activity are needed to define patient heterogeneity and identify mechanisms that could enable selection of targeted, personalized therapies; monitor changes in the immune state associated with responses to treatment, and serve as surrogate outcomes to shorten the duration of clinical trials. To fill this gap we have employed an array-based bioassay, where subject serum/plasma is used to induce transcriptional responses in a well-controlled peripheral blood mononuclear cell population. We find that pre and new onset T1D plasma induces a disease-specific, partially interleukin (IL)-1 dependent signature relative to related and unrelated healthy controls. We have used this approach to study participants of the IL- 1 antagonism trials and the TrialNet CTLA4-Ig trial. Our analyses revealed that varying levels of the anticipated immunomodulation was achieved with these immunotherapies. Notably, plasma induced transcription defined T1D subgroups, where those with the highest inflammatory bias prior to treatment, experienced the greatest post-onset decline in stimulated C-peptide area under the curve and the greatest therapeutic response. Overall, our data support the hypothesis that heterogeneity in inflammatory and regulatory activity at clinical onset can be used to stratify T1D patients into subgroups that differ in disease progression rate and responsiveness to immune intervention. We propose the following Specific Aims: Aim 1: To test the hypothesis that plasma induced signatures measured at baseline define ROT1D subgroups that predict the rate of post-onset C-peptide decline and therapeutic responsiveness. Aim 2: To test the hypothesis that T1D subgroups defined by plasma induced transcription exhibit distinct immunological phenotypes.

项目摘要/摘要 对1型糖尿病(T1D)发病机制的更好理解使 旨在诱导临床缓解的免疫调节策略。虽然已经学到了很多东西，但积极的 在这些试验中观察到的效果通常是有限的，患者的反应是 好坏参半。有人认为，这一结果是由于对 T1D发病机制的复杂性和异质性。需要新的免疫活性测量来确定 患者的异质性，并确定能够选择有针对性、个性化的机制 治疗；监测与治疗反应相关的免疫状态的变化，并作为 替代结果，以缩短临床试验的持续时间。 为了填补这一空白，我们采用了一种基于阵列的生物测定，其中受试者血清/血浆被用来诱导 受控良好的外周血单核细胞群体中的转录反应。我们发现Pre 新发病的T1D血浆诱导疾病特异性的、部分依赖白介素1的签名 相对于相关和非相关的健康对照。我们已经使用这种方法来研究IL-1的参与者- 1个拮抗试验和TrialNet CTLA4-Ig试验。我们的分析显示，不同水平的 预期的免疫调节是通过这些免疫疗法实现的。值得注意的是，等离子体诱导 转录定义了T1D亚组，在这些亚组中，治疗前炎症倾向最高的人， 发病后刺激C-肽曲线下面积下降幅度最大， 治疗反应。 总体而言，我们的数据支持这样的假设，即炎症和调控活动的异质性在 临床表现可以用来将T1D患者分成疾病进展不同的亚组 免疫干预的应答率和应答率。我们提出了以下具体目标： 目的1：验证在基线测量的血浆诱导信号定义ROT1D的假设 预测发病后C肽下降率和治疗反应性的亚组。 目的2：检验血浆诱导转录所定义的T1D亚群的假设 不同的免疫表型。