Obliterative bronchiolitis (OB) remains the principal cause of graft loss and death following lung transplantation. Here, we utilize a tolerogenic immunosuppressive regimen to determine whether the induction of a robust state of tolerance leads to the abrogation of OB in a partially-inbred miniature swine model.
Group 1 (control) consisted of recipients of class I-disparate lung allografts treated with a 12-day course of cyclosporine (∼10-13 mg/kg/d) (n = 6). Group 2 was comprised of similarly transplanted recipients treated with a 12-day course of high-dose tacrolimus (0.15 mg/kg/d) (n = 3). Group 3 consisted of recipients immunized with peptides derived from the donors’ class I MHC 21 days prior to transplantation, and then treated similarly with tacrolimus. 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.
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.
This study demonstrates that robust tolerance can be achieved using a clinically practical induction regimen. Furthermore, this state of tolerance can be induced in recipients previously sensitized to donor antigen, and is not broken by repeat exposure to donor antigen following transplantation. Most importantly, these data demonstrate that transplantation tolerance abrogates the development of OB.
We are currently extending these findings to fully mismatched allografts, and anticipate that the induction of tolerance will be an important therapeutic strategy in the prevention of OB without the requirement of chronic immunosuppression.
James Allan, None.