Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts.
BACKGROUND
Obliterative bronchiolitis remains a major long-term complication after lung transplantation. Using a reproducible model of heterotopically transplanted rat tracheas, this study examined the role of several novel immunosuppresive compounds to prevent and reverse obliterative airway disease in these animals.


METHODS
Brown Norway rat trachea were transplanted into the greater omentum of Lewis (allografts) or Brown Norway (isografts) animals. Recipient animals were treated with rapamycin, cyclosporine, 15-deoxyspergulin, mycophenolate 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 lumenal occlusion, as well as percent and type of lumen epithelial cell coverage.


RESULTS
All untreated allografted tracheas obliterated completely, although isografts appeared patent with normal respiratory epithelium when they were 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 mycophenolate mofetil failed to consistently inhibit obliteration with any treatment schedule. An inverse correlation was found between epithelial coverage and degree of obliteration, and was especially pronounced in grafts from cyclosporine-treated animals.


CONCLUSIONS
Immunosuppressive drug therapy will inhibit airway obliteration, but efficacy sharply diminishes if initiation of treatment is delayed. Efficacy also varies among immunosuppressive compounds, and results indicate those drugs that enable epithelial regrowth most effectively inhibit airway graft obliteration.
Adams
B F
BF
Department of Cardiothoracic Surgery, Stanford University School of Medicine, California 94305-5407, USA.
Berry
G J
GJ
Huang
X
X
Shorthouse
R
R
Brazelton
T
T
Morris
R E
RE
D000818:Animals; D004359:Drug Therapy, Combination; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D011183:Postoperative Complications / Q000188:drug therapy* / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012140:Respiratory Tract Diseases / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents