Apoptosis and rejection in rat intestinal, transplantation: Correlation with FK 506 doses and donor specific bone marrow infusions

Background. Our purpose was to investigate the occurrence and the evolution of apoptosis of enterocytes during acute and chronic rejection in an exper imental model of allogeneic heterotopic small bowel transplantation (SBTx). Methods. Forty-five rats were divided in 10 experimental groups according t o the dose of FR506 administration and donor bone marrow infusions (DBMI). Groups 1 and 2 did not received BMI. Groups 3 and 4 received 150x10(6) cell s at day 0, groups 5 and 6 received 75x10(6) cells at days 0-4, groups 7 an d 8 received 75x10(6) cells at days 4 and 10, and groups 9 and 10 received 30x10(6) cells at days 4, 10, 15, 20, and 25. Animals of groups 1, 3, 5, 7, and 9 were immunosuppressed with 0.5 mg/kg FK 506, although the remaining groups with 1 mg/kg FK 506, from day 0 to 4 after transplant. Fragment end labeling of DNA was used to detect apoptosis. Results. The number of apoptotic cells detected was highest at day 15 (184/-154) and then progressively decreased thereafter (day 30=159+/-197; day 4 5=80+/-167; day 60=0). The number of apoptotic enterocytes was found increa sed during mild (151+/-108) and moderate (281+/-161) allograft rejection, a lthough a low apoptotic rate was observed in cases without rejection (59+/- 13) and during severe (53+/-131) and chronic rejection (46+/-136). Furtherm ore the number of labeled cells was found inversely correlated with fibrosi s (P<0.0001). There was no correlation between apoptosis and the presence o r absence of DBMI; however, at day 15 rats receiving 1 mg/day of FK 506 had a significantly lower number of apoptotic cells detected (127+/-103 vs. 23 3+/-174; P<0.02). Conclusions. In this study the number of apoptotic cells correlated positiv ely with mild and moderate rejection episodes, In case of severe and chroni c rejection a low apoptotic rate was found due probably to extensive necros is and fibrosis of the mucosa. These data suggest an important role of apop tosis in acute and chronic intestinal rejection in a rat model of intestina l transplantation. Determination of apoptosis in allografts might represent an early sign of small bowel rejection and a useful marker in defining the degree of rejection and its outcome/prognosis.