Nomoto, M

Reynolds, JC

Starzl, TE

Sugitani, A

Todo, S

English

PubMed

Name not available

Intestinal neurons in acute and chronic rejection after small bowel transplantation in dogs

D-Scholarship@Pitt

Intestinal Neurons in Acute and Chronic Rejection After Small Bowel Transplantation in Dogs A. Sugitani, J.e. Reynolds, M. Nomoto, T.E. Starzl, and S. Todo THE mechanisms responsible for the altered neuromus-1. cular activity that results in the impaired motility of small bowel transplant recipients are incompletely under-stood. Autotransplantation studies in small l or large2 ani-mals have shown that harvesting process, preservation, and reperfusion may impair the function of the enteric nervous system during small bowel transplantation. It is not known, however, whether the immunologic events and vasculopa-thy that occur during acute and chronic rejection cause further damage to the enteric nervous system. MATERIALS AND METHODS Jejunal and ileal specimens were obtained from seven normal dogs autotransplanted (auto-Tx) at five intervals: 7 days (n = 6), 1 (n = 7),3 (n = 6),6 (n = 6), and 12 (n = 6) months. In alIotransplanted (alIo-Tx) models, the entire length of jejunum and ileum was flushed and switched between two dogs simultaneously. For the acute rejection model (n = 8), no immunosuppression was given. A laparotomy was performed to remove specimens 7 to 11 days postoperatively, when the dog showed general weakness, persistent vomiting, severe diarrhea, or bloody stool. The other allo-Tx group survived more than 2 months with an FK 506 maintenance dose of 0.1 mg/kg. When they presented with clinical signs of rejection. general weakness, abdominal distention, persistent vomiting, se-vere diarrhea. or more than 30% loss of body weight. dogs underwent laparotomy with inhalation anesthesia and had speci-mens removed. The presence of chronic rejection was conclusively determined by histopathologic analysis including the presence of a hallmark change of obliterative arteriopathy.3 Tissues in the studies were obtained from five dogs fit to this criteria. ranging from 80 to 696 postoperative days. Indirect immunohistochemistry was used to examine the inten-sity of tyrosine hydroxylase (TH) as an example of an extrinsic neuron. Neuropeptide Y (NPY), substance P (SP). and calcitonin gene-related peptide (CGRP) staining of neurofibers had mixed extrinsic and intrinsic origins. Vasoactive intestinal peptide (VIP). galanin (GAL). gastrin-releasing peptide (GRP). L-enkephalin (L-ENK). and somatostatin (SOM) neurons were examined as examples of intrinsic neurons. Results were expressed on a quali-tative scale of 0 to +3 in seven separate intestinal fields. Nitric oxide synthase histochemistry using the NADPH diaphorase tech-nique was used to examine the intensity and morphology of the myenteric plexus. and expressed as the number of positive nerve cells per ganglion area evaluated. RESULTS TH immunoreactivity in the myenteric plexus and in the muscle layers was reduced to + I in the auto-Tx 12-month Transplantation Proceedings, Vol 28, No 5 (October), 1996: p 2543 group, and 0 to essentially absent in specimens showing acute rejection. One dog showing chronic rejection had scanty extrinsic reinnervation. The other extrinsic markers including NPY, SP, and CGRP perivascular fibers also showed a similar pattern. VIP reactivity in the myenteric plexus, muscle layers, submucosal plexus, and villi showed a similar pattern in normal and auto-Tx groups. Acute rejec-tion severely reduced VIP expression. There was only + 1 fibers in the myenteric plexus, and no evidence of VIP fibers in the muscle layers. In chronic rejection, VIP fibers in the myenteric plexus and muscle layers showed only + 2 to + 1 staining. Other intrinsic and mixed fibers reactive to SP, GAL, GRP, L-ENK, and SOM as well as VIP showed a similar decreased immunoreactivity. No differences were seen in the density of NO-containing neurons in the myen-teric plexus in auto-Tx groups compared to normal dogs. During acute rejection, severe damage to NO neurons occurred, with most specimens showing no cells with NO (8.46 vs 66.64 in auto-Tx 7 days, P < .0001), and rare fibers. In chronic rejection, the number of NO-positive cells was also significantly decreased compared to auto-Tx dogs at 3, 6, or 12 months, which are the time consistent controls (37.5 vs 81.7 at 6 months, P = .007). CONCLUSIONS These findings indicate that acute and chronic rejection involve the enteric nervous system and cause significant widespread and nonspecific changes including damage to NO neurons when compared to autotransplantation. Thus, altered intestinal function in acute and chronic rejection is also mediated by damage to intrinsic neurons. REFERENCES 1. Lee KKW, et al: Transplantation 59:159, 1995 2. Nakada K, et al: Am J Surg 169:294, 1995 3. Demetris AJ, Zerbe T, Banner B: Transplant Proc 21:3667, 1989 From the Transplantation Institute, Departments of Medicine and Pathology, University of Pittsburgh, Pittsburgh, Pennsylva-nia. Address reprint requests to A. Sugitani, 3601 Fifth Avenue, Falk Clinic 4C, Pittsburgh, PA 15213. © 1996 by Appleton & Lange 0041-13451961$3.001 +0 2543 

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Intestinal neurons in acute and chronic rejection after small bowel transplantation in dogs

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