The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection.

Objectives-The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. We have induced robust tolerance to class I-disparate lung allografts in miniature swine using an intensive 12-day course of tacrolimus. Here, we test whether a tolerant state can be induced in swine receiving fully mismatched lung allografts.Methods-Orthotopic left lung allografts were performed using MHC class I-disparate (Group 1: n = 3) or fully disparate (Group 2: n = 6) donors. The recipients received a 12-day post-operative course of tacrolimus (continuous IV infusion; target level = 35-50 ng/ml) as their only immunosuppression.Results-All swine in Group 1 maintained their grafts long term without developing any lesions of chronic rejection (> 497, > 432, and > 451 days). These recipients exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity (CML) and mixed lymphocyte reaction (MLR) assays. In Group 2, 5 of the 6 recipients maintained their grafts long term (sacrificed on PODs 515, 389, 429, 481, and 438 with viable grafts). Isolated lesions of obliterative bronchiolitis (OB) were occasionally seen on biopsy, and donor-specific hyporesponsiveness on MLR and CML assays was consistently observed. The remaining recipient rejected its graft on POD 103 with histologic findings of OB.Conclusions-We now report long-term graft acceptance without chronic immunosuppression in 5 of 6 recipients across a full MHC disparity, albeit with some evidence of OB. These data suggest that the class II disparity inherent in a fully mismatched transplant increases the requirement for tolerance induction.

The authors' outcomes demonstrated that the HULA technique was a safe and effective approach for the complete correction of frontonasoethmoidal encephalomeningoceles.