Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
JCI Insight. 2019 Apr 9;5(9):125317. doi: 10.1172/jci.insight.125317.
Imatinib (Gleevec) reverses type 1 diabetes (T1D) in NOD mice and is currently in clinical trials in individuals with recent-onset disease. While research has demonstrated that imatinib protects islet β cells from the harmful effects of ER stress, the role the immune system plays in its reversal of T1D has been less well understood, and specific cellular immune targets have not been identified. In this study, we demonstrate that B lymphocytes, an immune subset that normally drives diabetes pathology, are unexpectedly required for reversal of hyperglycemia in NOD mice treated with imatinib. In the presence of B lymphocytes, reversal was linked to an increase in serum insulin concentration, but not an increase in islet β cell mass or proliferation. However, improved β cell function was reflected by a partial recovery of MafA transcription factor expression, a sensitive marker of islet β cell stress that is important to adult β cell function. Imatinib treatment was found to increase the antioxidant capacity of B lymphocytes, improving reactive oxygen species (ROS) handling in NOD islets. This study reveals a novel mechanism through which imatinib enables B lymphocytes to orchestrate functional recovery of T1D β cells.
伊马替尼（格列卫）可逆转 NOD 小鼠的 1 型糖尿病（T1D），目前正在发病初期的个体中进行临床试验。虽然研究表明伊马替尼可保护胰岛β细胞免受内质网应激的有害影响，但免疫系统在其逆转 T1D 中的作用尚未得到充分理解，也未确定特定的细胞免疫靶点。在这项研究中，我们证明了 B 淋巴细胞（一种通常驱动糖尿病病理的免疫亚群）出乎意料地是伊马替尼治疗的 NOD 小鼠逆转高血糖所必需的。在 B 淋巴细胞存在的情况下，逆转与血清胰岛素浓度的增加有关，但与胰岛β细胞质量或增殖的增加无关。然而，β细胞功能的改善反映在 MafA 转录因子表达的部分恢复上，MafA 转录因子是胰岛β细胞应激的敏感标志物，对成年β细胞功能很重要。研究发现伊马替尼治疗可增加 B 淋巴细胞的抗氧化能力，改善 NOD 胰岛中的活性氧（ROS）处理。这项研究揭示了一种新的机制，通过该机制，伊马替尼使 B 淋巴细胞能够协调 T1D β细胞的功能恢复。
