Clinical and Experimental Endocrinology, Chrometa, KU Leuven, Leuven, Belgium.
Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
Diabetes. 2023 Oct 1;72(10):1470-1482. doi: 10.2337/db22-0852.
Immunomodulation combined with antigen therapy holds great promise to arrest autoimmune type 1 diabetes, but clinical translation is hampered by a lack of prognostic biomarkers. Low-dose anti-CD3 plus Lactococcus lactis bacteria secreting proinsulin and IL-10 reversed new-onset disease in nonobese diabetic (NOD) mice, yet some mice were resistant to the therapy. Using miRNA profiling, six miRNAs (i.e., miR-34a-5p, miR-125a-3p, miR-193b-3p, miR-328, miR-365-3p, and miR-671-3p) were identified as differentially expressed in plasma of responder versus nonresponder mice before study entry. After validation and stratification in an independent cohort, plasma miR-193b-3p and miR-365-3p, combined with age and glycemic status at study entry, had the best power to predict, with high sensitivity and specificity, poor response to the therapy. These miRNAs were highly abundant in pancreas-infiltrating neutrophils and basophils with a proinflammatory and activated phenotype. Here, a set of miRNAs and disease-associated parameters are presented as a predictive signature for the L. lactis-based immunotherapy outcome in new-onset type 1 diabetes, hence allowing targeted recruitment of trial participants and accelerated trial execution.
Low-dose anti-CD3 combined with oral gavage of genetically modified Lactococcus lactis bacteria secreting human proinsulin and IL-10 holds great promise to arrest autoimmune type 1 diabetes, but the absence of biomarkers predicting therapeutic success hampers clinical translation. A set of cell-free circulation miRNAs together with age and glycemia at baseline predicts a poor response after L. lactis-based immunotherapy in nonobese mice with new-onset diabetes. Pancreas-infiltrating neutrophils and basophils are identified as potential cellular sources of discovered miRNAs. The prognostic signature could guide targeted recruitment of patients with newly diagnosed type 1 diabetes in clinical trials with the L. lactis-based immunotherapy.
免疫调节联合抗原治疗有望阻止自身免疫 1 型糖尿病，但由于缺乏预测生物标志物，临床转化受到阻碍。低剂量抗 CD3 联合分泌胰岛素原和白细胞介素 10 的乳球菌 Lactococcus lactis 逆转了非肥胖型糖尿病（NOD）小鼠的新发疾病，但有些小鼠对该疗法有抵抗力。使用 miRNA 谱分析，在研究开始前，在对治疗有反应的和无反应的小鼠的血浆中鉴定出六种 miRNA（即 miR-34a-5p、miR-125a-3p、miR-193b-3p、miR-328、miR-365-3p 和 miR-671-3p）存在差异表达。在独立队列中进行验证和分层后，血浆 miR-193b-3p 和 miR-365-3p 与研究开始时的年龄和血糖状态相结合，具有最佳的预测能力，对治疗反应不良具有高灵敏度和特异性。这些 miRNA 在具有炎症和激活表型的胰腺浸润中性粒细胞和嗜碱性粒细胞中含量丰富。在这里，一组 miRNA 和与疾病相关的参数被提出作为基于乳球菌 Lactococcus lactis 的免疫治疗新诊断 1 型糖尿病结果的预测特征，从而允许有针对性地招募试验参与者并加速试验执行。
低剂量抗 CD3 联合口服灌胃分泌人胰岛素原和白细胞介素 10 的基因修饰乳球菌 Lactococcus lactis 有望阻止自身免疫 1 型糖尿病，但缺乏预测治疗成功的生物标志物阻碍了临床转化。一组无细胞循环 miRNA 与基线时的年龄和血糖一起预测了非肥胖型糖尿病新发病例中基于乳球菌 Lactococcus lactis 的免疫治疗后的不良反应。胰腺浸润的中性粒细胞和嗜碱性粒细胞被鉴定为发现的 miRNA 的潜在细胞来源。该预后特征可指导以新诊断 1 型糖尿病患者为目标的临床试验中基于乳球菌 Lactococcus lactis 的免疫治疗的靶向招募。
