Abstract
BackgroundRecent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown.Materials and MethodsFemale NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed.ResultsAG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system.ConclusionThe use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.
Highlights
Tyrosine phosphorylation inhibitors, termed tyrphostins, are a family of low molecular weight molecules having the ability to inhibit tyrosine phosphorylation through protein tyrosine kinases (PTKs)
AG490 significantly inhibited the development of type 1 diabetes (T1D) (p = 0.02, p = 0.005; at two different time points)
Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal
Summary
Tyrosine phosphorylation inhibitors, termed tyrphostins, are a family of low molecular weight molecules having the ability to inhibit tyrosine phosphorylation through protein tyrosine kinases (PTKs). AG490 has been widely studied in cancer and autoimmune diseases, but not subject to investigation in the setting of T1D. Tyrosine kinase inhibitors (TKIs) have been broadly used in many cancer clinical trials [2,3,4], T1D [5,6] in mouse model of multiple sclerosis [7] and in intestinal inflmmation is reported [8]. Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. The therapeutic effects of AG490 on the development of T1D are unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
