JAK3 INHIBITION WITH CP-690,550 PREVENTS OBLITERATIVE BRONCHIOLITIS IN A RAT TRACHEAL TRANSPLANT MODEL.

Abstract

O120 Aims: Specific targeting of the Janus kinase (JAK) 3 with the immunosuppressant CP-690,550 effectively prevents acute allograft rejection. Here we determined the efficacy of CP-690,550 in a rat model of tracheal transplant-associated obliterative bronchiolitis (OB) and studied its effects on platelet-derived growth factor (PDGF), a major mitogen that has been shown to play an important role in OB. Methods: Tracheal segments from Brown Norway or Lewis rats were transplanted subcutaneously in Lewis rats. Recipients (n=4-6 per group) were either untreated (isografts or allografts) or treated with CP-690,550 (allografts). One group of recipients was treated for 28 days with sirolimus (SRL). Tracheal grafts harvested at 7, 14 or 28 days were processed for conventional histology, morphometric analysis and RNA extraction. Results: Untreated allografts developed typical features of OB by day 28, which included airway obliteration (90% vs. 2.7% luminal obliteration for isografts, p<0.001) and epithelial loss (0% vs. 100% epithelial coverage for isografts, p<0.001). Treatment with CP-690,550 significantly prevented airway obliteration (2.5% luminal obliteration, p<0.001 vs. untreated allografts) and loss of epithelial coverage (100% epithelial coverage present in all grafts) at 28 days and this effect was already significant at day 14. A moderate spindle cell infiltrate seen in 90% of untreated allografts on day 28 was absent in most grafts (83.3%) from CP-690,550-treated animals. Similar results were noted with SRL. Lymphocytic and macrophage infiltration was low to nonexistent in isografts at 28 days, while untreated allografts showed mild to high lymphocytic and macrophage infiltration. Grafts from animals treated with CP-690,550 consistently showed minimal lymphocytic and macrophage infiltration at 28 days. PDGF gene expression in untreated allografts was characterized by a transient (day 14) reduction in PDGF-A expression, no significant change in PDGF-B expression and a late (> day 14) significant over expression of PDGFR-α and PDGFR-β. No significant differences in the expression of any of these genes were noted between untreated and treated allografts at the time points studied. Conclusions: This is the first demonstration of the effectiveness of JAK3 blockade by CP-690,550 in the prevention of transplant-associated OB in an animal model. Results suggest that JAK3 blockade by CP-690,550 prevents transplant-associated OB via mechanisms that are independent or downstream from PDGF signals. Additional studies are underway to further elucidate the mechanisms by which CP-690,550 inhibits OB.