Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice.
Here we show that Janus kinase (JAK) 3 is an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes. Whereas 60% of vehicle-treated control NOD mice became diabetic by 25 weeks, the incidence of diabetes at 25 weeks was only 9% for NOD females treated with daily injections of JANEX-1 (100 mg/kg/day) from Week 10 through Week 25 (P = 0.007). Furthermore, JANEX-1 prevented the development of insulitis and diabetes in NOD-scid/scid females after adoptive transfer of splenocytes from diabetic NOD females. Chemical inhibitors such as JANEX-1 may provide the basis for effective treatment modalities against human type 1 diabetes. To our knowledge, this is the first report of the immunosuppressive activity of a JAK3 inhibitor in the context of an autoimmune disease.
Cetkovic-Cvrlje
Marina
M
Department of Immunology, Parker Hughes Institute, 2699 Patton Road, St. Paul, MN 55113, USA.
Dragt
Angela L
AL
Vassilev
Alexei
A
Liu
Xing-Ping
XP
Uckun
Fatih M
FM
D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007376:Interleukin-2 / Q000494:pharmacology; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008894:Milk Proteins; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D050799:STAT5 Transcription Factor; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D008894:Milk Proteins; D011799:Quinazolines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C116180:WHI P131; D014443:Tyrosine; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3