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

Abstract

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. 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. 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. 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.