Total orthotopic allogeneic small bowel transplantation in rats: effect of allograft irradiation combined with cyclosporine-A therapy.

Abstract

Rejection and graft versus host disease are prominent features in small bowel allotransplantation in rats. Cyclosporine treatment of the recipient and irradiation of the donor were used to circumvent these phenomena in the WAG to brown Norway rat model. Irradiation ofthe donor with five or 10 Gy did prevent graft versus host disease but resulted in a more vigorous rejection of small bowel aliografts in untreated recipients (mean (SEM) survival times of 11.5 (0.4) (n=8) and 7*5 (0.9) (n=11) days respectively, versus 16.6 (2.6) days (n=17), p<001 Various experimental studies on the rejection of small bowel allografts have shown that under certain immunological conditions, immunocompetent cells in these grafts can cause graft versus host disease (GVHD).' While the occurrence of this reaction in well defined inbred systems has been conclusively documented, its importance in outbred systems is uncertain. In a previous study we successfully ameliorated GVHD in the WAG to BN rat model using whole body irradiation of the donor with 10 Gy.5 The effectiveness of donor irradiation had been shown previously in a parent to Fl hybrid rat model in which the donors were irradiated with 7, 9.5, and 10 Gy before small bowel transplantation.267 In this study we investigated the effects of combined cyclosporine treatment and donor irradiation because we had evidence that irradiation of the donor leads to accelerated rejection of the graft.5 We wondered whether cyclosporine could reverse this effect. Earlier we found that cyclosporine, used alone, was not effective in consistently producing long term survivors in the WAG to BN donor-host combination.8 In this study we show that the effect of cyclosporine on GVHD is less pronounced than its effect on rejection, as shown earlier by Kirkman.9 In large animal models cyclosporine proved to be less successful than in certain rat strain combinations.'7 Two recent studies in pigs, using ex vivo irradiation of the transplant with 0.5 Gy, a very low dose, combined with cyclosporine therapy of the recipient showed no effect on host survival time compared with cyclosporine monotherapy.'89 Because the immunological problems of large animal models resemble the problems in our WAG to BN rat model, this model is highly suitable for investigating the effect of irradiation combined with cyclosporine treatment. Methods ANIMALSA fully allogeneic donor-host model was employed by using inbred WAG (RT1u) rats as donors and inbred BN (RTLn) rats as recipients. The rats weighed between 200-350 g. OPERATIVE PROCEDURESDonors were fasted for 24 to 48 hours with water ad libitum. All procedures were performed under ether anaesthesia. The method of orthotopic small bowel transplantation has been published recently.5 Briefly, the small bowel was double tied and cut 1 cm distally to the ligament of Treitz and 1-2 cm proximally to the cxcum. The graft was harvested along with the attached vascular pedicles, consisting of the portal vein and the superior mesenteric artery, including an aortic cuff. The graft...

Effects of donor pretreatment with antilymphocyte serum and cyclosporin on rejection and graft-versus-host disease after small bowel transplantation in immunosuppressed and nonimmunosuppressed rats

“…When our recipients of a graft pretreated with ALS received immunosuppressive treatment with CyA, no adverse effect on graft survival was seen anymore, whereas clinical GVHD remained suppressed. This important finding is in accordance with earlier findings from our laboratory that show that irradiation of the donor with 5 or 10 Gy eliminated clinical GVHD and led to significantly accelerated graft rejection [18]. When recipients of a graft that was irradiated with 5 or 10 Gy received immunosuppressive treatment with CyA, graft survival was prolonged in both groups, whereas clinical GVHD did not occur.…”

“…We have shown that irradiation of the donor with 5 or 10 Gy prevents the occurrence of clinical GVHD and leads to accelerated graft rejection. This study also gave indirect evidence that subclinical GVHD may benefit graft survival [18]. However, most studies on GVHD following small bowel transplantation have used…”

Small bowel transplantation: an overview

“…When our recipients of a graft pretreated with ALS received immunosuppressive treatment with CyA, no adverse effect on graft survival was seen any more, whereas clinical GVHD remained suppressed. This important finding is in accordance with earlier findings from our laboratory [115]. The usefulness of manipulating this balance for future clinical SBT remains to be established since it is as yet unclear whether this balance theory is a rat strain-dependent phenomenon and whether GVHD will even be a clinical problem.…”

“…We showed that irradiation of the donor with 10 Gy 1 day before fully allogeneic SBT in the WAG-to-BN rat model completely eliminated GVHD and significantly shortened survival times [114]. Moreover, CyA treatment of the recipient was unable to completely override this effect [115]. Pretreatment of the donor with ALS also eliminated clinical GVHD and led to significantly accelerated rejection [12].…”