1. Soluble CD137 Ameliorates Acute Type 1 Diabetes by Inducing T Cell Anergy.
- Author
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Itoh A, Ortiz L, Kachapati K, Wu Y, Adams D, Bednar K, Mukherjee S, Chougnet C, Mittler RS, Chen YG, Dolan L, and Ridgway WM
- Subjects
- Animals, Cell Cycle, Cytokines metabolism, Diabetes Mellitus, Type 1 immunology, Female, Immunologic Memory, Insulin metabolism, Insulin-Secreting Cells metabolism, Interleukin-2 immunology, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Inbred NOD, Signal Transduction, T-Lymphocyte Subsets metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 9 antagonists & inhibitors, Tumor Necrosis Factor Receptor Superfamily, Member 9 genetics, Tumor Necrosis Factor Receptor Superfamily, Member 9 immunology, CD4-Positive T-Lymphocytes immunology, Clonal Anergy immunology, Diabetes Mellitus, Type 1 therapy, Tumor Necrosis Factor Receptor Superfamily, Member 9 therapeutic use
- Abstract
We show here that soluble CD137 (sCD137), the alternately spliced gene product of Tnfsfr9 , effectively treats acute type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. sCD137 significantly delayed development of end-stage disease, preserved insulin+ islet beta cells, and prevented progression to end-stage T1D in some mice. We demonstrate that sCD137 induces CD4+ T cell anergy, suppressing antigen-specific T cell proliferation and IL-2/IFN-γ secretion. Exogenous IL-2 reversed the sCD137 anergy effect. sCD137 greatly reduces inflammatory cytokine production by CD8 effector memory T cells, critical mediators of beta cell damage. We demonstrate that human T1D patients have decreased serum sCD137 compared to age-matched controls (as do NOD mice compared to NOD congenic mice expressing a protective Tnfsfr9 allele), that human sCD137 is secreted by regulatory T cells (Tregs; as in mice), and that human sCD137 induces T cell suppression in human T cells. These findings provide a rationale for further investigation of sCD137 as a treatment for T1D and other T cell-mediated autoimmune diseases., (Copyright © 2019 Itoh, Ortiz, Kachapati, Wu, Adams, Bednar, Mukherjee, Chougnet, Mittler, Chen, Dolan and Ridgway.)
- Published
- 2019
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