Thomas Pech¹, Ichiro Ohsawa¹, Michael Praktiknjo¹, Kareem Abu-Elmagd², Joerg C. Kalff¹, Nico Schaefer¹

¹Department of Surgery, University of Bonn, Bonn, Germany; ²Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States

Introduction: The small intestine is highly immunogenic and there is rising evidence that recurrent ACR episodes may trigger chronic rejection, having influence on the long term outcome. Infliximab is established in therapy of inflammatory bowel diseases, and it has been reported as successful rescue therapy for resistant rejection after small bowel transplantation. This study evaluated the effects of additional infliximab application during rescue therapy with tacrolimus basic immunosuppression to reveal mechanistical causes of this phenomenon.

Methods: Orthotopic allogeneic intestinal transplantation was performed in rats. Immunosuppression with Tacrolimus 2mg/kg/day was started on POD1 (group 1/continuous immunosuppression) or POD7 after manifestation of acute rejection. Animals were sacrificed on POD7 (group 2/acute rejection, no treatment), POD14 (group 3/immunosuppression) and POD21 (group 4/immunosuppression) during the recovery process. Additional infliximab treatment was administered on POD7 conjointly with tacrolimus. Animals were sacrified on POD14 (group 5/immunosuppression) or POD21 (group 6/immunosuppression).

Results: Tacrolimus and the combination therapy presented with steady, but not entirely, improved histological grading scores, accompanied by less leukocyte infiltration in the muscle layer. The mRNA-expression of proinflammatory cytokines and chemotactic mediators in the muscle layer revealed recovery in all groups treated with tracrolimus similar to combined treatment with infliximab except significantly increased levels of CD4, FOXP3 and IL-17 (mRNA) at POD 14 in the combination therapy group. Enteric nerve recovery was enhanced by infliximab about 25% compared to tacrolimus only. Smooth muscle function improved from 60% (group 6) to 45% (group 4) reduction compared to non-transplanted controls.

Conclusions: Recovery from acute rejection progresses steady but slowly after starting immunosuppressive therapy as rescue therapy. Additional infliximab treatment enhances the physiological recovery of the muscle layer and enteric nervous system independent from inflammatory reactions. The improved smooth muscle function may prevent from postoperative ileus and possible successive bacterial overgrowth and translocation after small bowel transplantation.