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

 描述(由申请人提供)：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的开发成为可能。虽然已经学到了很多，但在这些试验中观察到的积极影响通常是有限的，患者的反应也是喜忧参半。需要新的免疫活性测量来确定能够选择有针对性的个性化治疗的机制；监测与治疗反应相关的免疫状态的变化，并作为替代结果来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/血浆被用来在受控良好的外周血单核细胞群中诱导转录反应。我们发现，与相关和不相关的健康对照相比，发病前和新发的T1D血浆诱导了疾病特异性的、部分依赖白介素1(IL-1)的签名。我们用这种方法研究了白介素1在糖尿病中的作用和TrialNet Canakinumab试验的参与者。总体而言，这些试验没有显示IL-1受体拮抗剂(IL-1RA)或Canakinumab治疗在保留T1D患者β细胞功能方面的有效性。然而，我们的分析表明，无论是治疗还是治疗，预期的免疫调节程度都不同，并且在炎症标志和刺激的C-肽曲线下区域之间观察到相反的关系。我们假设，将这种方法应用于临床试验，代表了除IL-1拮抗之外的一系列免疫调节策略，将允许1)在每个研究中对治疗反应进行分子定义；以及2)确定炎症状态的机械相似变化是否有助于整个试验的积极反应。我们提出以下具体目标：目的1：通过对参加GAD-明矾免疫试验的RO T1D患者的时间分析，确定与靶抗原免疫相关的分子特征。目的：通过对参加MMF/DZB和CTLA-4-Ig(Abatacept)试验的RO T1D患者的时间分析，确定与免疫细胞复制/相互作用障碍相关的分子特征。目的：通过对参加抗CD20(利妥昔单抗)试验的RO T1D患者的时间分析，确定与B淋巴细胞消融相关的分子特征。

 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.