THE ROLE OF HOST THYMIC FUNCTION IN THE INDUCTION OF TOLERANCE ACROSS FULL MHC BARRIERS BY FK506

Abstract

P929 Aims: Previous studies have demonstrated the importance of an intact thymus in induction of tolerance to class I-mismatched renal allografts by Cyclosporin in miniature swine. A short course of FK506 has subsequently been shown to induce tolerance to fully mismatched renal allografts in this large animal model. In the present study, we assessed whether thymectomy likewise interferes with induction of this tolerance. Methods: Recipients of fully MHC disparate renal allografts were treated with a 12-day course of FK506 (0.15 mg/kg/day by continuous i.v. infusion), with doses adjusted to maintain trough levels of 30-50 ng/ml. Four experimental animals were thymectomized 21 days prior to transplantation, while two control animals remained euthymic. Tolerance was tested in vivo in animals with surviving grafts at day 100 by re-transplantation using another donor-matched kidney and no immunosuppression. Results: Both euthymic controls accepted their renal allografts for >100 days and accepted second grafts long-term with stable renal function. They also demonstrated donor-specific hypo-responsiveness in CML and MLR assays and showed no evidence of IgG or IgM deposition in kidney biopsies, confirming that they were tolerant. In contrast, all four thymectomized recipients developed evidence for acute and chronic rejection. The first animal rejected its graft on day 17, autopsy demonstrating a swollen and necrotic graft with patent vessels. The second animal maintained its kidney >100 days, but rejected a second donor-matched allograft acutely on day 20. The third animal was euthanized on day 99 due to chronic rejection with unstable renal function. The fourth animal accepted both its first and second renal allografts, but remnants of the native thymus were detected on autopsy, indicating incomplete thymectomy. In vitro assays of the first three (but not the fourth) animals demonstrated responsiveness to donor MHC by CML and MLR and both IgG and IgM deposition were found in the kidneys histologically. Conclusions: The host thymus is required for induction of transplant tolerance across a two-haplotype full MHC barrier by a short course of FK506, although even a small amount of thymic tissue may be sufficient to provide the required thymic function.