Journal of Clinical Immunology

, Volume 32, Issue 5, pp 1038–1047

Tyrphostin AG490 Agent Modestly but Significantly Prevents Onset of Type 1 in NOD Mouse; Implication of Immunologic and Metabolic Effects of a Jak-Stat Pathway Inhibitor

Authors

    • Department of Pharmacotherapy and Translational ResearchCollege of Pharmacy
    • Brain Endowment Bank, Department of Neurology, Miller School of MedicineUniversity of Miami
  • Azadeh Hassanzadeh
    • Department of Pharmacotherapy and Translational ResearchCollege of Pharmacy
  • Clive H. Wasserfall
    • Department of Pathology, Immunology and Laboratory Medicine, College of MedicineUniversity of Florida
  • Andrew Droney
    • Department of Pharmacotherapy and Translational ResearchCollege of Pharmacy
  • Mark Atkinson
    • Department of Pathology, Immunology and Laboratory Medicine, College of MedicineUniversity of Florida
Article

DOI: 10.1007/s10875-012-9707-y

Cite this article as:
Davoodi-Semiromi, A., Hassanzadeh, A., Wasserfall, C.H. et al. J Clin Immunol (2012) 32: 1038. doi:10.1007/s10875-012-9707-y

Abstract

Previously, we have reported that the Jak-Stat signaling pathway is defective in NOD mice. In this study, prediabetic female NOD mice (4 weeks) were treated by intraperitoneal injection either with AG490 or DMSO three times per week for 4 consecutive weeks, followed by once a week for an additional 6 weeks. The onset of diabetes was attenuated in NOD mice treated with AG490 relative to DMSO treated control mice (p < 0.02). From an immunological standpoint, AG490 induced the expression of Foxp3 in CD4+CD25 T-cells and down-regulated expression of co-stimulatory molecules in dendritic cells (DC) both in vitro and in vivo. AG490 treated CD4+CD25− T-cells and DC in vitro, acquired regulatory functions; namely, the ability to suppress proliferation of a responding cell population in vitro. AG490 treatment resulted in significant reduction of blood glucose values and increased expression of PPARγ in splenocytes and markedly increased expression PPARγ2 but not PPARγ1 in adipocyte in vitro. Presence of multiple Stat5 DNA binding consensus sequences within the promoter region of the PPARγ gene in human and in mouse suggests that PPARγ is downstream to the Jak-Stat signaling pathway. This study highlights a critical role of the Jak-Stat signaling pathway in the pathogenesis of T1D and suggests that blocking the Jak-Stat signaling pathway by AG490 as a tyrosine kinase inhibitor may provide an effective means for preventing autoimmune T1D via both immunological and metabolic effects.

Keywords

Type 1 diabetes tyrosine kinase inhibitor AG490 regulatory T-cell NOD

Supplementary material

10875_2012_9707_MOESM1_ESM.docx (14 kb)
ESM 1 (DOCX 14 kb)

Copyright information

© Springer Science+Business Media, LLC 2012