Plasma Induced Signatures as a Measure of Immunomodulation in T1D Clinical Trials

血浆诱导特征作为 T1D 临床试验中免疫调节的衡量标准

• 批准号: 9319744
• 负责人: Martin J Hessner
• 金额: $ 30.4万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-21 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319744
• 关键词: Ablation; Age; Antigen Targeting; Area Under Curve; Autoantibodies; Autoimmunity; B-Lymphocytes; Beta Cell; Biological Assay; Blinded; C-Peptide; CTLA4-Ig; Cell physiology; Clinical; Clinical Trials; Daclizumab; Dependency; Development; Diabetes Mellitus; Disease; Disease Progression; Equilibrium; FOXP3 gene; Failure; Family; Frequencies; Future; Genetic Transcription; Haplotypes; Immune; Immunization; Immunologics; Impairment; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-1; Interleukin-1 Receptors; Interleukin-10; Knowledge; Lead; Longitudinal Studies; MS4A1 gene; Measurement; Measures; Mediating; Molecular; Molecular Profiling; Monitor; Newly Diagnosed; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Plasma; Population; Positioning Attribute; Predisposition; Rattus; Regulatory T-Lymphocyte; Reporting; Serum; Siblings; Structure of beta Cell of islet; Surrogate Endpoint; T-Lymphocyte; Testing; Therapeutic; Transcript; Transforming Growth Factor beta; Virus Diseases; aluminum sulfate; anakinra; arm; base; clinical efficacy; clinical remission; high risk; immunoregulation; improved; insight; insulin dependent diabetes mellitus onset; intervention effect; mycophenolate mofetil; novel; personalized medicine; polypeptide C; proband; public health relevance; responders and non-responders; response; rituximab; treatment response

 DESCRIPTION (provided by applicant): 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. New measures of immune activity are needed to define 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 thi 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 Interleukin-1 in Diabetes Action and TrialNet Canakinumab trials. Overall, these trials did not show efficacy of IL-1 receptor antagonist (IL-1RA) or canakinumab therapy in preserving β-cell function in T1D patients. However, our analyses revealed that varying levels of the anticipated immunomodulation was achieved with either therapeutic and an inverse relationship was observed between the inflammatory signature and stimulated C-peptide area under the curve. We hypothesize that application of this approach to clinical trials representing a spectrum of immunomodulatory strategies beyond IL-1 antagonism will allow 1) a molecular definition of the therapeutic response within each study; and 2) a determination whether mechanistically similar alterations in the inflammatory state contributed to positive responses across the trials. We propose the following Specific Aims: Aim 1: To define the molecular signature associated with target antigen immunization through temporal analysis of RO T1D patients participating in the GAD-alum immunization trial. Aim 2: To define the molecular signatures associated with impairment of immunocyte replication/interaction through temporal analysis of RO T1D patients participating in the Mycophenolate Mofetil-Daclizumab (MMF/DZB) and CTLA-4-Ig (Abatacept) trials. Aim 3: To define the molecular signature associated with B-lymphocyte ablation through temporal analysis of RO T1D patients participating in the anti-CD20 (Rituximab) trial.