Epithelial re-growth is associated with inhibition of obliterative airway disease in orthotopic tracheal allografts in non-immunosuppressed rats.
BACKGROUND
Because epithelial cells are targets of alloimmune injury leading ultimately to airway obliteration, we tested whether epithelial re-growth could prevent obliterative airway disease (OAD) in orthotopic tracheal allografts.


METHODS
Brown Norway tracheal segments were orthotopically transplanted into nonimmunosuppressed Lewis rats. Allografts were removed on days 2-10 (n=13), 30 (n=4), and 60 (n=5) for histology, computerized morphometry (obliteration), and immunohistochemical detection of mononuclear cells, smooth muscle alpha-actin, and tissue phenotype. Normal tracheas, host tracheas, and heterotopically transplanted allografts served as controls.


RESULTS
Orthotopic allografts removed on days 2-10 exhibited epithelial damage and re-growth and mononuclear cell infiltration. On days 30 and 60, partially ciliated cuboidal or attenuated epithelium completely covered the lumen. Although mononuclear cells declined, numerous T cells with a high CD4/CD8 ratio were found in the epithelium till day 60. Orthotopic allograft epithelium expressed donor phenotype on day 7, but recipient phenotype on days 30 and 60. Despite subepithelial alpha-actin positive myofibroblast proliferation, obliteration did not progress from day 7 to 30 and 60 (35, 30, and 33%, respectively). Although more than in normal or host tracheas, the obliteration in orthotopic allografts on days 30 and 60 was significantly less (P<0.001) than in heterotopic allografts.


CONCLUSIONS
We describe, for the first time, longterm patency of fully histoincompatible orthotopic tracheal allografts in nonimmunosuppressed rats. Despite acute alloimmune injury and induction of myofibroblast proliferation, epithelial re-growth from the host limited the progression of OAD, thus emphasizing the role of epithelium in the control of airway obliteration.
Ikonen
T S
TS
Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA 94305-5407, USA.
Brazelton
T R
TR
Berry
G J
GJ
Shorthouse
R S
RS
Morris
R E
RE
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D016516:CD4-CD8 Ratio; D007108:Immune Tolerance / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D010641:Phenotype; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020545:Respiratory Mucosa / Q000254:growth & development* / Q000378:metabolism; D014132:Trachea / Q000473:pathology / Q000637:transplantation*; D014184:Transplantation, Homologous / Q000276:immunology*