Apoptosis and rejection in rat intestinal transplantation: correlation with FK506 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 experimental model of allogeneic heterotopic small bowel transplantation (SBTx).


METHODS
Forty-five rats were divided in 10 experimental groups according to the dose of FK506 administration and donor bone marrow infusions (DBMI). Groups 1 and 2 did not received BMI. Groups 3 and 4 received 150x106 cells at day 0, groups 5 and 6 received 75x106 cells at days 0-4, groups 7 and 8 received 75x106 cells at days 4 and 10, and groups 9 and 10 received 30x106 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 45=80+/-167; day 60=0). The number of apoptotic enterocytes was found increased during mild (151+/-108) and moderate (281+/-161) allograft rejection, although a low apoptotic rate was observed in cases without rejection (59+/-13) and during severe (53+/-131) and chronic rejection (46+/-136). Furthermore the number of labeled cells was found inversely correlated with fibrosis (P<0.0001). There was no correlation between apoptosis and the presence or 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. 233+/-174; P<0.02).


CONCLUSIONS
In this study the number of apoptotic cells correlated positively with mild and moderate rejection episodes. In case of severe and chronic rejection a low apoptotic rate was found due probably to extensive necrosis and fibrosis of the mucosa. These data suggest an important role of apoptosis in acute and chronic intestinal rejection in a rat model of intestinal 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.
Vennarecci
G
G
University of Miami School of Medicine, Liver and GI Transplant Program, Division of Transplantation, Highland Professional Building, 1801 NW 9th Avenue, Miami, FL 33136, USA.
Berho
M
M
Sommariva
A
A
Neto
A B
AB
Misiakos
E P
EP
Inverardi
L
L
Ruiz
P
P
Ricordi
C
C
Tzakis
A G
AG
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D016559:Tacrolimus / Q000008:administration & dosage* / Q000627:therapeutic use; D014019:Tissue Donors
D007166:Immunosuppressive Agents; D016559:Tacrolimus