B lymphocytes protect islet β cells in diabetes-prone NOD mice treated with imatinib
Christopher S. Wilson, … , Roland W. Stein, Daniel J. Moore
Christopher S. Wilson, … , Roland W. Stein, Daniel J. Moore
Published May 2, 2019; First published April 9, 2019
Citation Information: JCI Insight. 2019;4(9):e125317. https://doi.org/10.1172/jci.insight.125317.
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Research Article Metabolism

B lymphocytes protect islet β cells in diabetes-prone NOD mice treated with imatinib

Abstract

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 expression of the transcription factor MafA, a sensitive marker of islet β cell stress that is important for adult β cell function. Imatinib treatment was found to increase the antioxidant capacity of B lymphocytes, improving ROS handling in NOD islets. This study reveals a mechanism through which imatinib enables B lymphocytes to orchestrate functional recovery of T1D β cells.

Authors

Christopher S. Wilson, Jason M. Spaeth, Jay Karp, Blair T. Stocks, Emilee M. Hoopes, Roland W. Stein, Daniel J. Moore

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Figure 1

In vivo imatinib injections target B lymphocytes that are essential for diabetes reversal in NOD mice.

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In vivo imatinib injections target B lymphocytes that are essential for ...
(A) Analysis of splenocytes revealed a reduction in total splenocyte numbers in NOD mice following imatinib treatment. ***P = 0.022, Student’s t test. (B) B lymphocytes were preferentially depleted in NOD mice (**P = 0.041, Student’s t test) as compared with T lymphocytes (P = 0.071, Student’s t test). n = 5 per group, representative of 5 experimental replicates. (C) B220 MACS-depleted splenocytes (10 × 106) from a diabetic NOD donor mouse were transferred into immunodeficient NOD.Rag1–/– mice. Mice were allowed to become diabetic, and at time of diabetes onset were given imatinib injections alone, 20 × 106 B cell–depleted splenocytes and imatinib, or 20 × 106 MACS-purified B lymphocytes and imatinib. (D) Blood glucose levels of diabetic mice on imatinib therapy revealed that only mice that received B lymphocytes and imatinib together had normalization of blood glucose. n = 15 in the group that received no additional cells, n = 6 in the group that received additional non-B lymphocytes, n = 29 in the group that received additional B lymphocytes. **P = 0.002, Mantel-Cox log-rank test. Data compiled from 5 separate experiments shown in C.