title: The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice.
abstract: BACKGROUND
  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. However, the therapeutic effects of AG490 on the development of T1D are unknown.
  
  
  METHODS
  Female 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.
  
  
  RESULTS
  AG490 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America. dsemiromi@cop.ufl.edu
authors.forename: Abdoreza
authors.initials: A
authors.lastname: Davoodi-Semiromi
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.forename: Chang Qing
authors.initials: CQ
authors.lastname: Xia
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Michael
authors.initials: M
authors.lastname: Clare-Salzler
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000517:prevention & control*; D005260:Female; D051379:Mice; D016688:Mice, Inbred NOD; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012074:Remission Induction; D013154:Spleen / Q000166:cytology; D013311:Streptozocin; D020032:Tyrphostins / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D013311:Streptozocin; D011505:Protein-Tyrosine Kinases