Role of the thymus in transplantation tolerance in miniature swine - III. Surgical manipulation of the thymus interferes with stable induction of tolerance to class I-mismatched renal allografts

Background Previous studies have demonstrated that long-term tolerance of c lass I mismatched renal allografts in miniature swine is induced by a short course of cyclosporine (CyA), and that a total thymectomy 21 days before t ransplantation abrogates the induction of stable tolerance. We have now exa mined the effects of surgical manipulation of the thymus, with or without a reduction in the thymic volume, on the induction of tolerance. Materials and Methods. Miniature swine receiving a transplant of a class I- mismatched renal allograft and 12 days of CyA underwent either (1) a partia l thymectomy 21 days before kidney transplantation (day -21), (2) serial th ymic biopsies (to evaluate the effect of surgical trauma and reduction in v olume of the thymus) or serial incisions of the thymus thymus (to evaluate the effect of surgical trauma without changes in thymic volume), (3) a sham thymectomy on day -21, or serial sham thymic surgery on the same POD as th e thymic biopsies and incisions (control animals), Results. Control animals had a stable plasma creatinine, had donor-specific unresponsiveness in cell-mediated lympholysis (CML) assays, had absence of rejection in kidney biopsy specimens, and did not develop anti-donor class I immunoglobulin (Ig)G alloantibodies. Animals undergoing a partial thymec tomy on day -21 or serial thymic biopsies showed severe renal dysfunction, histological evidence of rejection in kidney biopsy specimens and anti-dono r reactivity in CML assays; all but one animal developed anti-donor class I IgG alloantibodies. Serial incisions of the thymus induced an increase in plasma creatinine and histological rejection in 1 of 3 animals and anti-don or cytotoxic T cells in vitro in all 3 animals, Conclusions. A partial thymectomy or serial thymic biopsies markedly interf ere with the induction of tolerance to renal allografts, Serial thymic inci sions also interfere with the induction of tolerance, but to a lesser degre e, These studies may have implications for tolerance-inducing protocols tha t involve thymic manipulation.