Chronic rejection causes early destruction of the intrinsic nervous system in rat intestinal transplants

Abstract

Chronic rejection is the major cause of late intestinal allograft dysfunction. We have previously shown that chronic rejection alters the muscularis externa of the graft. This study determined structural and functional changes to the enteric nerves during chronic rejection. Chronic rejection was achieved in orthotopic intestinal transplants (ACI to Lewis) by limited immunosuppression. Syngeneic transplants (ACI to ACI) and unoperated ACI rats served as controls. Animals were clinically healthy and showed no significant alterations in the mucosal architecture on postoperative day 90. Staining for NADPH diaphorase activity (nitric oxide synthase-containing neurons) and with neurofilament antibody RT-97 revealed that chronic rejection decreased the number of jejunal myenteric ganglia by approximately 50%. Inhibitory junction potentials (IJPs) to circular muscle cells were determined by electrical field stimulation (EFS). In controls and syngeneic grafts, EFS caused a stimulus-dependent increase in IJP amplitude, with a maximal amplitude of 9 +/- 0.4 and 10 +/- 0.8 mV, respectively. Chronic rejection in allografts markedly increased the threshold for IJP initiation and decreased the maximal IJP amplitude (5 +/- 0.8 mV). Our data indicate that chronic rejection severely damages the muscularis and the enteric nervous system before mucosal changes become evident.