Journal article

The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-gamma and Common gamma Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice

Tingting Ge, Gaurang Jhala, Stacey Fynch, Satoru Akazawa, Sara Litwak, Evan G Pappas, Tara Catterall, Ishan Vakil, Andrew J Long, Lisa M Olson, Balasubramanian Krishnamurthy, Thomas W Kay, Helen E Thomas

FRONTIERS IN IMMUNOLOGY | FRONTIERS MEDIA SA | Published : 2020

Abstract

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8+ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JA..

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Grants

Awarded by Juvenile Diabetes Research Foundation (JDRF)


Awarded by National Health and Medical Research Council of Australia


Funding Acknowledgements

This work was funded by the Juvenile Diabetes Research Foundation (JDRF, SRA-2018-599-S-B), the National Health and Medical Research Council of Australia (GNT1126237 and GNT1150425) and fellowships from the JDRF and Manpei Suzuki Diabetes Foundation (SA). The St Vincent's Institute receives support from the Operational Infrastructure Support Scheme of the Government of Victoria.