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Repetitive Gastric Aspiration Leads to Augmented Indirect Allorecognition after Lung Transplantation in Miniature Swine

Gregory Veillete, MD, Andrew J. Meltzer, MD, Matthew J. Weiss, MD, Bruce R. Rosengard, MD, Joren C. Madsen, MD, D.Phil, James S. Allan, MD
Massachusetts General Hospital; Boston, MA


PURPOSE OF STUDY
Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration following allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition.

METHODS USED:
Left orthotopic lung transplants (n=3) were performed in miniature swine across an MHC class I disparity, followed by 12 days of high-dose cyclosporine (CyA). At the time of transplantation, a trans-tracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3cc/hr x 8hr/day) for 50 days. Recipients were followed with daily CBC, scheduled chest radiographs, and biopsies. In vitro studies, including CML, MLR, and peptide proliferation assays (PPA), were performed. Results from these three recipients were compared to those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration.

SUMMARY OF RESULTS:
Two of the experimental animals were sacrificed with non-viable lungs soon after the POD 50 biopsy. In both cases the native lung was normal. The third animal survived to 180 days without evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (CML, MLR). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported.

CONCLUSIONS:
A large-animal model of GERD after lung transplantation resulted in a spectrum of clinical outcomes. The in vitro data suggest that acid reflux enhances the indirect alloresponse to processed donor class I antigen, giving mechanistic insight into the manner in which GERD may be deleterious to the transplanted lung.

 

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