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: 9912933
• 负责人: Martin J Hessner
• 金额: $ 52.34万
• 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/9912933
• 关键词: Antigens; Archives; 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; 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; 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.

项目总结/文摘