COMBINED TRANSPLANTATION OF SMALL AND LARGE-BOWEL - FK506 VERSUS CYCLOSPORINE-A IN A PORCINE MODEL

Clinically, FK506 is superior to CsA after solitary small bowel transp lantation (SBTx). Development of diarrhea after SBTx has been the rati onale for adding the colon to small bowel grafts. However, the additio nal lymphoid and bacterial content transferred with total small plus l arge bowel transplants (TBTx) might aggravate the alloimmune response- rejection and graft-versus-host disease (GVHD)-and increase the risk o f infection. We studied the incidence of rejection, GVHD, and infectio n after TBTx and the impact of CsA versus FK506. We performed orthotop ic TBTx with portal drainage after total enterectomy in outbred Yorksh ire Landrace pigs, divided into 3 groups: control pigs (n=6) received no immunosuppression; CsA pigs (n=14) received CsA (5 mg/kg), antilymp hocyte globulin (10 mg/kg for 10 days), prednisone (2 mg/kg), and AZA (2.5 mg/kg); and FK506 pigs (n=9) received FK506 (0.2 mg/kg) and predn isone (2 mg/kg). Trough CsA whole blood levels were >400 ng/ml for the first 7 days and >200 ng/ml thereafter. FK506 levels were >15 ng/ml. We excluded from further analysis 5 early deaths (<3 days) due to anes thesiologic (n=2) or technical reasons (n=3). Median survival of contr ol pigs was 9.5 days (range, 4-13). Cyclosporine did not extend surviv al: median, 9 days (range, 5-31) (P=0.6), FK506 prolonged survival: me dian, 37 days (range, 21-49) (P<0.001 vs. control and CsA pigs). Of FK 506 pigs, 60% gained weight (+75 g/day), whereas 100% of controls and 75% of CsA pigs lost weight (-550 g/day and -300 g/day, respectively). All control pigs died of rejection within 2 weeks versus none of the FK506 pigs. However, 36% of CsA pigs died of rejection. Groupwise comp arison showed less rejection in FK506 versus control pigs (P<0.001) an d in FK506 versus CsA pigs (P<0.03), but no difference between CsA and control pigs. None of the control pigs died of GVHD versus 18% of CsA pigs (by day 31) and 37% of FK506 pigs (by day 49). Groupwise compari son showed increased GVHD in FK506 versus control pigs (P<0.001) and a tendency toward increased GVHD in FK506 versus CsA pigs (P=0.08). Non e of the control pigs died of infection alone versus 22% of CsA pigs ( by day 31) and 67% of FK506 pigs (by day 49). Groupwise comparison sho wed increased infection in FK506 versus control pigs (P<0.001). We det ected significant endotoxemia early and late postoperatively. But we s aw no specific correlation between endotoxemia, rejection, GVHD, or in fection. Based on this study, we have drawn several conclusions: (1) I n untreated pigs, TBTx provokes a severe rejection response, but no le thal GVHD. (2) Cyclosporine and particularly FK506 pigs have a high in cidence of infection and lethal GVHD, a complication that we had not s een after solitary SBTx. (3) FK506 is superior to CsA in controlling r ejection and in prolonging graft and recipient survival; FK506, howeve r, does not reduce GVHD, but rather tends to augment it. (4) TBTx caus es endotoxemia. As with solitary SBTx, FK506 is superior to CsA after TBTx. However, long-term survival is difficult to achieve in FK506 rec ipients because of the development of GVHD and infection.