INDUCTION OF TRANSPLANTATION TOLERANCE WITH A SHORT COURSE OF TACROLIMUS(FK506)

Publisher Website
Google Scholar
Abstract
Background. Inbred miniature swine provide a large animal model inwhich the effects of selective major histocompatibility complex (MHC) matchingcan be reproducibly studied. We have previously demonstrated that although a12-day course of cyclosporine uniformly induces tolerance to classI-mismatched renal allografts, it does not induce tolerance across full MHCbarriers. In this study, we assessed whether and at what dose tacrolimus mightpermit allografts to induce tolerance across different MHCbarriers. Methods. Recipients of MHC disparate renal allografts were treatedwith a 12-day course of tacrolimus by continuous intravenous infusion. Groupswere divided as follows: (1) class I-mismatched kidneys with 0.3 mg/kg/daytacrolimus (n=3); (2) fully MHC-mismatched kidneys with 0.3 mg/kg/daytacrolimus (n=2); and (3) fully MHC-mismatched kidneys with0.12–0.16 mg/kg/day tacrolimus(n=4). Results. In groups 1 and 2, recipients with tacrolimus levels of45–80 ng/ml accepted renal allografts long-term with stable renalfunction. Donor-specific hyporesponsiveness was demonstrated by cell-mediatedlymphocytotoxicity and mixed lymphocyte response, and subsequent donor-matchedgrafts were also accepted, without further immunosuppression (n=4),confirming systemic tolerance. In group 3, recipients that achieved tacrolimuslevels of 35 ng/ml (n=2) accepted their grafts without chronic changes,whereas recipients with levels of 20–26 ng/ml (n=2) developedchronic allograft glomerulopathy, suggesting 35 ng/ml as the threshold bloodlevel for tolerance induction. In vitro assays demonstrated that peripheralblood lymphocytes from tolerant animals produced inhibitory cytokines,suggesting the involvement of regulatorymechanisms. Conclusions. To our knowledge, this study represents the firstdemonstration of the induction of transplant tolerance across a two-haplotypefull MHC barrier with a short course of immunosuppression in a large animalmodel. These studies may also have clinical applicability, because the timecourse required to induce tolerance was sufficiently short that the high druglevels required might be expected to be tolerated clinically with onlytransienttoxicity.