The influence of surgery, immunosuppressive drugs, and rejection, on graft function after small bowel transplantation: a large-animal study

Abstract

In this study we assessed functional changes (motility and absorption) of intestinal allografts in a large-animal model of orthotopic small bowel transplantation in swine. Studies were performed on non-rejecting animals in the early and late stages after transplantation and after induction of different grades of acute rejection. Immunosuppression consisted of oral FK506 and mycophenolate mofetil. In each study group we regulated drug administration, in terms of dosage and timing, in order to induce different grades of acute rejection or to prevent it. Migrating myoelectrical complexes were recorded in fasting animals so that motility could be assessed. Mucosal biopsy of the allograft and D-xylose absorption tests were performed on the same day as the motility study. In the early stages following intestinal transplantation, we observed in non-rejecting animals a slightly increased graft motility and a marked carbohydrate malabsorption. Recovery of the carbohydrate absorption capacity occurs within 2 months, but the persistence of diarrhea leads to partial malabsorption and to a lack of normal weight gain. Motility reduction correlates with the grade of acute rejection and becomes significant at a later stage, when rejection is severe. Allograft carbohydrate absorption, on the contrary, is markedly reduced in all rejecting pigs, irrespective of the grade of rejection. In summary, the early functional impairment of non-rejecting animals has multifactorial causes due to surgery and immunosuppression (drug toxicity), and its occurrence suggests the need for specific guidelines for clinical early postoperative enteral feeding. The functional studies adopted here are helpful in defining the grade of functional impairment with or without acute rejection; however, they are not useful for early detection of ongoing acute rejection of the small bowel graft.

Skin biopsies predict acute graft-versus-host disease after small bowel transplantation in pigs

“…Although the pathohistological changes are well known (Przepiorka et al, 1994;Alessiani et al, 1996a;Paulsen, 2000;Alessiani et al, 2003;Cahn et al, 2005), the exact immunological mechanism is not clear. Interestingly, however, the skin histopathological findings after Itx are similar to acute GVHD skin changes after bone marrow transplantation.…”

“…Orthotopic small intestinal transplantation (Starzl et al, 1992;Alessiani et al, 1996a;Alessiani et al, 2003) was performed. The intestinal graft was composed with the proximal jejunum just after the ligament of Treitz and 20 cm proximal to the ileocaecal valve and the superior mesenteric artery and vein.…”

“…The histological criteria established for the grading of small bowel allograft acute rejection were used (Wu et al, 2003). We used (Table 1) an already described grading system for acute skin GVHD (Kerr et al, 2000;Gulbahce et al, 2003;Alessiani et al, 2003;Cahn et al, 2005;McKee et al, 2005). Table 1 Histological criteria for the grading of acute GVHD in the skin Histological analysis was performed by a trained pathologist blinded to the treatment protocols.…”

FK506 treatment in a Long-term chronic rejection rat model of small bowel transplantation

“…[6][7][8][9] Other immunosuppressants or combination of drugs were tried but the results were contradictory. 13 Murase et al 8 performed OSBT from Brown Norway to Lewis rats underwent a short course of FK506 treatment (1mg/kg/day, POD0-13, 20, 27): all recipients survived over 150 days but CR was severe in the intestine. The BN-to-Lewis rat strain combination is strongly histoincompatible which led to severe rejection, while F344-to-LEW rat inbred strain combination showed less histoincompatible, so the doses of FK506 in our study should be lower.…”

Surgical Technique of Small Bowel Transplantation in a Large Animal Model

“…Upon fixation with formalin, biopsy specimens were embedded in paraffin using standard method and stained with haematoxylin-eosin. To assess the extent of rejection-induced injury, the criteria related to experiments with large animals in modification incorporating experience from human pathology were used (Murase et al 1990;Alessiani et al 2003;Ruiz et al 2004). Morphological features of acute cellular rejection (ACR) included the presence of inflammatory cellulization in the mucosal lamina propria in combination with varying degrees of crypt damage.…”