Abstract
Background: The effects of costimulatory blockade in a large animal model of cardiac transplantation are not well-established. We have previously shown that CTLA4Ig, but not anti -CD154 mAb, blocks in vitro T cell costimulation in the miniature swine. In this report, we have examined the effects of costimulatory blockade on graft rejection and cardiac allograft vasculopathy (CAV) in a MHC (SLA in swine) class I-disparate model of cardiac transplantation using MHC-inbred miniature swine. Methods: SLAdd (IdIId) miniature swine received class I-mismatched SLAgg (IcIId) heterotopic cardiac allografts . Four experimental protocols were administered: (1) anti-CD154 mAb (20 mg/kg QOD, POD 0-12) alone, (2) anti-CD154 mAb (10 mg/kg QOD, POD 0-12) plus donor-specific transfusion (DST), (3) CTLA4Ig (5 mg/kg QOD, POD 0-12) alone, (4) CTLA4Ig (10 mg/kg POD 0, 5 mg/kg QD POD 1-14) plus DST. Untreated and cyclosporine (10 mg/kg iv QD, POD 0-11) treated transplant recipients were used as controls. Results: Untreated recipients of class I-disparate cardiac allografts rejected their hearts acutely by POD 7. CyA-treated pigs rejected class I-disparate hearts with a MST of 55 days and develop CAV by the 4th week post-transplant. Anti-CD154 mAb alone or in combination with DST did not prevent acute rejection of class I-disparate cardiac allografts, as grafts were rejected on day 10 and day 8. In addition, CTLA4Ig alone only prolonged survival to 16 days. Recipients developed anti-donor antibodies and maintained strong anti-donor CTL responses. Moreover, these recipients were sensitized to polymorphic donor class I peptides through the indirect pathway based on peptide proliferation assays. In contrast, the combination of CTLA4Ig plus DST prolonged graft survival >75 days with donor-specific hyporesponsiveness on CML and donor peptide proliferation assays. Serial biopsies revealed mild to moderate interstitial rejection but no CAV. Conclusions: Induction therapy with CTLA4Ig plus DST, but not anti-CD154 mAb, prolonged survival of class I-disparate cardiac allografts in the miniature swine and delayed or prevented the development of CAV.
Published Version
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