Inhibition of obliterative airway disease development following heterotopic murine tracheal transplantation by costimulatory molecule blockade using anti-CD40 ligand alone or in combination with donor bone marrow.
BACKGROUND
Obliterative airway disease (OAD) development in heterotopic murine tracheal allografts, a model of obliterative bronchiolitis after lung transplantation, is immunologically mediated. Whether tolerance induction by the administration of anti-CD40 ligand monoclonal anti-body (MR-1) alone or in conjunction with donor-derived bone marrow cells (BMCs) can prevent the development of OAD was tested in this study.


METHODS
BALB/c tracheal allografts were heterotopically transplanted into C57BL/6 recipients. Group 1 received no treatment. Group 2 received multiple infusions of donor BMCs intravenously. Group 3 was administered MR-1 intraperitoneally. Group 4 received donor BMCs and MR-1. Allografts were harvested at several time points post-transplantation and examined for the development of OAD.


RESULTS
Group 1 developed cellular infiltration and epithelial damage by Day 15 post-transplant and OAD by Day 28, evidenced by complete obliteration of the tracheal lumen. Group 2 developed OAD with similar kinetics to Group 1. Group 3 had no evidence of OAD at 28 days. At Days 45 to 90, moderate cellular infiltration, epithelial metaplasia, and a minimal narrowing of the tracheal lumen were evident. OAD developed by Day 120. Group 4 mice had patent tracheal lumens even at 120 days post-transplantation, with only mild epithelial metaplasia and luminal narrowing noted.


CONCLUSIONS
The administration of MR-1 alone in combination with infusions of donor bone marrow cells significantly attenuated the development of OAD. Tolerance-inducing regimens such as this deserve further investigation in the prevention of post-lung transplant obliterative bronchiolitis following human lung transplantation.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Félix G
FG
Fernández
Brice
B
McKane
Shawn
S
Marshbank
G Alexander
GA
Patterson
Thalachallour
T
Mohanakumar
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D001989:Bronchiolitis Obliterans / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D046528:Chimerism; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D014132:Trachea / Q000637:transplantation*; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand