Repetitive gastric aspiration leads to augmented indirect allorecognition after lung transplantation in miniature swine.
BACKGROUND
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 after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition.


METHODS
Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal 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 (3 mL/hrX8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration.


RESULTS
Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). 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
In a model of GERD after lung transplantation, a spectrum of clinical outcomes was observed. 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.
Meltzer
Andrew J
AJ
Transplantation Biology Research Center, Massachusetts General Hospital Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Weiss
Matthew J
MJ
Veillette
Gregory R
GR
Sahara
Hisashi
H
Ng
Choo Y
CY
Cochrane
Meghan E
ME
Houser
Stuart L
SL
Sachs
David H
DH
Rosengard
Bruce R
BR
Madsen
Joren C
JC
Wain
John C
JC
Allan
James S
JS
D000818:Animals; D001706:Biopsy; D005764:Gastroesophageal Reflux / Q000209:etiology* / Q000473:pathology; D005774:Gastrostomy; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000276:immunology / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D016040:Lung Transplantation / Q000009:adverse effects* / Q000473:pathology / Q000502:physiology*; D013552:Swine; D013556:Swine, Miniature; D014184:Transplantation, Homologous / Q000473:pathology / Q000502:physiology*
D015395:Histocompatibility Antigens Class I