Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin, the Children's Research Institute of Children’s Hospital of Wisconsin, and theHuman and Molecular Genetics Center, Milwaukee, Wisconsin, USA.
Diabetes. 2010 Oct;59(10):2375-85. doi: 10.2337/db10-0372. Epub 2010 Aug 3.
Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions.
We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes in biobreeding (BB) rats.
Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors, and signaling molecules in PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1-regulated genes. Supplementing cultures with an IL-1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (P < 10(-6)), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (P = 0.007), and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immunoregulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation.
Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention.
与 1 型糖尿病相关的炎症介质在周围组织中含量较低且难以测量，因此需要开发更敏感和更具信息量的生物标志物来研究糖尿病发病机制、评估发病前风险和监测治疗干预效果。
我们之前利用了一种新的生物测定法，即用人 1 型糖尿病血清诱导与健康无关的外周血单个核细胞（PBMC）中特定的疾病转录特征。在此，我们应用该策略来研究生物繁殖（BB）大鼠 1 型糖尿病相关的炎症状态。
与它们共同的易感性一致，自发糖尿病 BB DRlyp/lyp 大鼠和可诱导糖尿病 BB DR+/+大鼠的血清与对照血清相比，可诱导健康供体大鼠的 PBMC 中细胞因子、免疫受体和信号分子的转录。与人类 1 型糖尿病特征相似，与进展为糖尿病相关的 DRlyp/lyp 特征与 DR+/+的特征不同，其特征在于许多白细胞介素（IL）-1 调节基因的诱导。在培养物中补充白细胞介素 1 受体拮抗剂（IL-1Ra）可调节 DRlyp/lyp 特征（P<10(-6)），而给予 DRlyp/lyp 大鼠 IL-1Ra 可延迟发病（P=0.007），且治疗动物的血清不会诱导特征性特征。与 DR+/+大鼠中存在免疫调节细胞一致的是，诱导的特征具有转录和炎症的负调节因子。
与我们的人类研究相平行，BB 大鼠的血清特征反映了与进展为 1 型糖尿病相关的过程。此外，这些研究支持了该方法在检测治疗干预期间炎症状态变化的潜在应用。
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