The selective jak1/3-inhibitor r507 mitigates obliterative airway disease both with systemic administration and aerosol inhalation
Spin, Joshua M.
Fink, James B.
Robbins, Robert C.
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Deuse, Tobias; Hua, Xiaoqin; Stubbendorff, Mandy; Spin, Joshua M. Neofytou, Evgenios; Taylor, Vanessa; Chen, Yan; Park, Gary; Fink, James B.; Renne, Thomas; Kiefmann, Martina; Kiefmann, Rainer; Reichenspurner, Hermann; Robbins, Robert C.; Schrepfer, Sonja (2016). The selective jak1/3-inhibitor r507 mitigates obliterative airway disease both with systemic administration and aerosol inhalation. Transplantation 100 (5), 1022-1031
Background. The efficacy of selective Janus kinase 1/3 inhibitor R507 to prevent obliterative airway disease was analyzed in preclinical airway transplantationmodels. Methods. Orthotopic trachea transplantations were performed between Lewis donors and Brown Norway rat recipients. Oral everolimus (4mg/kg once per day) or oral respective inhaled R507 (60mg/kg twice per day, each) was used for immunosuppression. Grafts were retrieved after 6 or 60 days. Toxicity and anti-inflammatory effects of R507 were analyzed on human airway epithelial cells. Results. In 6-day animals, oral and inhaled R507 more potently diminished mononuclear graft infiltration than everolimus and preserved ciliated pseudostratified columnar respiratory epithelium. Everolimus and R507 similarly suppressed systemic cellular and humoral immune activation. In untreated rats, marked obliterative airway disease developed over 60 days. Oral and inhaled R507 was significantly more effective in reducing airway obliteration and preserved the morphology of the airway epithelium. Luciferase-positive donors revealed that a substantial amount of smooth muscle cells within the obliterative tissue was of donor origin. Only everolimus but not R507, adversely altered kidney function and lipid profiles. The R507 aerosol did not show airway toxicity in vitro but effectively suppressed activation of inflammatory signaling pathways induced by IL-1 beta. Conclusions. The Janus kinase 1/3 inhibitor R507 is a very well-tolerated immunosuppressant that similarly diminished obliterative airway disease with systemic or inhaled administration.