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PREVENTION OF OBLITERATIVE AIRWAY DISEASE THROUGH TOLERANCE INDUCTION FOLLOWING CD40 COSTIMULATORY BLOCKADE IN COMBINATION WITH DONOR BONE MARROW CELL INFUSION.
F. Fernandez MD , B. McKane MD , A. Jaramillo PhD , G. A. Patterson, MD and T. Mohanakumar PhD . St. Louis MO, Washington University, 63110, Surgery .

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Introduction: Murine heterotopic tracheal allografts develop obliterative airway disease (OAD), a suitable model of chronic rejection following human lung transplantation (tx). Interaction of antigen presenting cell CD40 costimulatory molecules and its ligand, CD154 (CD40L), on activated T cells is important in immune responses to alloantigens. We hypothesized that tolerance induction with anti-CD40L mAb (MR-1) and donor bone marrow cell (BMC) infusions prevents OAD development.
Methods: Balb/c tracheas were heterotopically transplanted into C57BL/6 mice. Group 1 received no treatment. Group 2 received infusions of donor BMC on post-tx day 0, 2, 4, 6, 14, and 28. Group 3 received anti-CD40L mAb intraperitoneal on day 0, 2, 4, 6, 14, and 28. Group 4 received BMC and CD40L mAb. Grafts were harvested 15-90 days post tx and examined for OAD.
Results: Group 1 developed fibrous obliteration of the tracheal lumen by day 28. Group 2 developed OAD with similar kinetics to Group 1. Group 3 had no evidence of rejection at 28 days. By day 45 there was mild cellular infiltration and epithelial metaplasia which persisted at day 90. Group 4, receiving both BMC and anti-CD40L, had a completely patent tracheal lumen and only mild epithelial metaplasia noted at 90 days.
Conclusions: This study demonstrates that anti-CD40L significantly attenuates OAD development. Addition of donor BMC infusions along with anti-CD40L completely abrogates OAD development. This indicates that a tolerance inducing regimen can prevent development of OAD. T-cell costimulatory blockade appears important to tolerance induction with this regimen as evidenced by early development of OAD in mice given infusions of donor BMC alone.