The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia.
Janus kinase 3 (JAK-3) is a tyrosine kinase that has been shown to participate in the signaling of several cytokines that are believed to play a role in allergic airway disease, e.g. IL-2, 4 and 9. The current study describes the immunosuppressive effects of CP-690550, a novel, small molecule inhibitor of JAK-3, in a murine model of allergic pulmonary inflammation. In vitro, CP-690550 potently inhibited IL-4 induced upregulation of CD23 (IC(50)=57 nM) and class II major histocompatibility complex (MHCII) expression (IC(50)=71 nM) on murine B cells. Repeat aerosol exposure to ovalbumin in wild-type mice sensitized to the antigen resulted in preferential recruitment of Th2-like cells (IL-4+ and IL-5+) into bronchoalveolar lavage fluid (BAL). The importance of IL-4 in the development of pulmonary eosinophilia was supported by a marked (90%) reduction in the influx of these cells in IL-4KO mice similarly sensitized and ovalbumin exposed. Animals dosed with CP-690550 (15 mg/kg/d) during the period of antigen sensitization and boost demonstrated marked reductions in BAL eosinophils and levels of IL-13 and eotaxin following ovalbumin aerosol exposure. The JAK-3 inhibitor (1.5-15 mg/kg/d) also effectively reduced the same parameters when administered during the period of antigen challenge. In contrast, the calcineurin inhibitor tacrolimus (10 mg/kg) was effective only when administered during the period of ovalbumin aerosol exposure. These data support the participation of JAK-3 in processes that contribute to pulmonary eosinophilia in the allergic mouse model. CP-690550 represents an intriguing novel therapy for treatment of allergic conditions associated with airway eosinophilia including asthma and rhinitis.
Kudlacz
Elizabeth
E
Pfizer Global Research and Development, New London, CT 06320, USA. elizabeth.m.kudlacz@pfizer.com
Conklyn
Maryrose
M
Andresen
Catharine
C
Whitney-Pickett
Carrie
C
Changelian
Paul
P
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000276:immunology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010880:Piperidines; D011657:Pulmonary Eosinophilia / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D017455:Receptors, IgE / Q000096:biosynthesis; D018418:Th2 Cells / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000949:Histocompatibility Antigens Class II; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D017455:Receptors, IgE; D015847:Interleukin-4; C479163:tofacitinib; D010047:Ovalbumin; D053616:Janus Kinase 3