Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts

Background. Obliterative bronchiolitis remains a major long-term complicati on after lung transplantation. Using a reproducible model of heterotopicall y transplanted rat tracheas, this study examined the role of several novel immunosuppresive compounds to prevent and reverse obliterative airway disea se in these animals. Methods. Brown Norway rat trachea were transplanted into the greater omentu m of Lewis (allografts) or Brow Norway (isografts) animals. Recipient anima ls were treated with rapamycin, cyclosporine, 15-deoxyspergulin, mycophenol ate mofetil, or leflunomide from day 0, 7, or 14 until day of graft removal , either day 28 or 50, Trachea segments were evaluated for degree of lumena l occlusion, as well as percent and type of lumen epithelial cell coverage. Results. All untreated allografted tracheas obliterated completely, althoug h isografts appeared patent with normal respiratory epithelium when they we re removed. Leflunomide, rapamycin, and cyclosporine effectively prevented obliteration when treatment was initiated at day 0, with rapamycin showing continued efficacy when initiated as late as day 7, 15-Deoxyspergulin and m ycophenolate mofetil failed to consistently inhibit obliteration with any t reatment schedule, An inverse correlation was found between epithelial cove rage and degree of obliteration, and was especially pronounced in grafts fr om cyclosporine-treated animals. Conclusions. Immunosuppressive drug therapy will inhibit airway obliteratio n, but efficacy sharply diminishes if initiation of treatment is delayed. E fficacy also varies among immunosuppressive compounds, and results indicate those drugs that enable epithelial regrowth most effectively inhibit airwa y graft obliteration.