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The Induction of Robust Tolerance in an MHC-Mismatched Porcine Pulmonary Allograft Model Prevents Obliterative Bronchiolitis

Hisashi Sahara, Tsuyoshi Shoji, Ashok Muniappan, Dax A. Guenther, John C. Wain, Stuart L. Houser, Akshat Pujara, Marjory A. Bravard, David H. Sachs, Joren C. Madsen, James S. Allan
Massachusetts General Hospital, Boston, MA

Objective: To determine whether the induction of tolerance abrogates obliterative bronchiolitis (OB).
Design and Setting: Controlled experimental trial.
Animals: Donor-recipient pairs of MHC class I-mismatched miniature swine.
Intervention: Group 1 (control) - recipients of lung allografts treated with a 12-day course of postoperative cyclosporine (~10-13 mg/kg/d) (n = 6). Group 2 - recipients treated with a 12-day course of high-dose tacrolimus (0.15 mg/kg/d). Group 3 - tacrolimus-treated recipients immunized prior to transplantation with peptides derived from the donors’ class I MHC (n = 3). All recipients were monitored for the development of OB by serial open lung biopsy, and long-term acceptors (>350 days) were challenged with skin grafting prior to sacrifice.
Main Outcome Measures: Graft survival and presence of OB.
Results: In Group 1, 4/6 developed OB within 8 months. In Group 2, all swine maintained their grafts for > 497, > 451, and > 432 days. In Group 3, grafts survived for >417, >402, >374 days. Some lung grafts in Groups 2 and 3 had transient mononuclear cellular infiltrates; but none developed OB on multiple biopsies. All recipients exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity.
Conclusions: Robust tolerance can be achieved using a clinically practical regimen. Furthermore, this state of tolerance can be induced in recipients that have been previously sensitized, and is not broken by repeat exposure to donor antigen following transplantation. Most importantly, the achievement of transplantation tolerance abrogates the development of OB.

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