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Objectives: The purpose of this study was to establish a safe technique to procure liver grafts from marginal donors such as non-heart-beating donors (NHBD)., Materials and Methods: Male Wistar rats were divided into five groups: (1) heart-beating (HB) group, livers were retrieved from HB donors; (2) non-HB (NHB) group, livers were retrieved from uncontrolled NHBD that had experienced the apnea-induced agonal condition; (3) nafamostat mesilate (NM) group, livers retrieved in the same manner as NHBD but pretreated with NM (0.2 mg/kg/h for 30 minutes); (4) prostaglandin I2 (PG) group, livers retrieved in the same manner as NHBD but pretreated with the (33 ng/kg/h, for 30 minutes); (5) NM + PG group, livers retrieved the same manner as NHBD but pretreated with NM and PG. After 1-hour cold preservation, the organs were transplanted according to Kamada's method. We examined aspartate transferase (AST) alanine transferase (ALT), lactate dehydrogenase, interleukin-1 beta, tumor necrosis factor-alpha, and thromboxane B2 (TXB2) at 24 hours after transplantation. We also performed histological examinations using electron microscopy., Results: The number of survivors at 7 days after liver transplantation among the groups were 9/9, 0/9, 1/9, 1/9, and 3/9. The values of AST, ALT, and lactate dehydrogenase at 24 hours after transplantation in the NM + PG groups were slightly lower than those in the NHB group, but there were no significant differences among those groups. On the histological examination, the NM + PG group showed well-preserved sinusoidal endothelial cells., Conclusion: The strong serine protease inhibitor, NM, and PG may support sinusoidal endothelial cells, a promising strategy for liver transplantation from marginal donors.

Antibody-mediated acute rejection (AbAR) is one of the primary causes of graft impairment in kidney transplant recipients. Deoxyspergualin (DSG), which displays an antiproliferative action against antigen-stimulated B cells inhibiting antibody production, may be effective to rescue AbAR in combination with plasmapheresis by suppressing antibody production and elimination. In the present study, we report our experience with DSG/plasmapheresis therapy for the treatment of AbAR. Five kidney transplant patients experienced a steroid-resistant acute rejection requiring dialysis followed by an AbAR that was confirmed by biopsy and flow cytometry crossmatch (FCXM) results. DSG was administration at 3 mg/kg per day for 10 days with plasmapheresis reduce antidonor antibody. Treatment outcome, effectiveness, and adverse events were examined; in two cases sequential FCXM examinations were performed to evaluate antibody status. All five patients received DSG/plasmapheresis therapy. The number of plasmapheresis treatments ranged from 1 to 9 according to treatment outcomes. Four patients recovered graft function following treatment; whereas one showed no response to the treatment, and the graft was lost. No serious side effects or infections were observed during or after treatment. Monitoring of sequential FCXM correlated with the clinical course. AbAR shows a worse prognosis than cellular rejection. It is refractory to conventional antirejection therapy. In the present study, DSG/plasmapheresis therapy was effective in four of five patients (80%) with AbAR. It may be considered the first choice of treatment for cases of acute humoral rejection.

Background: We examined whether deoxyspergualin (DSG) prophylaxis in combination with cyclosporine (CsA)- or tacrolimus (Tac)-based immunosuppression augments the effect of donor-specific blood transfusions (DSTs) to improve long-term survival of living-related renal-transplants., Methods: From May 1985 to January 1998, 176 patients received DST from one-haplotype-identical donors prior to kidney transplantation. Group A (n = 64, 1985 to 1989) received CsA, prednisolone (PSL), antilymphocyte globulin (ALG), and azathioprine (AZA). Group B (n = 89, 1989 to 1996) received CsA, PSL, ALG, and DSG. Group C (n = 23, 1996 to 1998) received Tac, PSL, ALG, and DSG, with DSG followed by AZA. Rejection episodes were classified as acute rejection (AR, within the first 3 months) or late acute rejection (LAR, from 4 months to 1 year)., Results: Five-year graft survivals were 73.4%, 88.8%, and 91.3% for groups A, B, and C, respectively. The incidence of AR was 34%, 30%, and 13%, and that of LAR was 23%, 26%, and 30% for groups A, B, and C, respectively. There was no significant difference in the incidence of AR or LAR among the three groups. However, an elevated serum creatinine (sCr) > or =1 mg/dL was observed in 73%, 15%, and 0% of patients during AR, and in 53%, 30%, and 14% during LAR for groups A, B, and C, respectively. These results suggest that the severity of AR or LAR was lowest among group C, contributing to the improved long-term graft survival in these patients., Conclusions: DSG prophylaxis with Tac-based immunosuppression further improves long-term graft survival among living-related renal-transplant recipients treated with DST by decreasing the severity of acute rejection episodes.

Background: CTLA4 immunoglobulin (CTLA4 Ig), which binds with high affinity to B7-1 and B7-2, interrupts T-cell activation by inhibiting the costimulatory signal. CTLA4Ig has been used to achieve antigen-specific tolerance induction in cardiac allografts. On the other hand, we have shown that short-term administration of deoxyspergualin (DSG) and daily cyclosporine (CsA) induces long-term survival of cardiac xenotransplants. We hypothesized that the combination therapy of DSG and adenovirus-mediated CTLA4IgG might induce long-term, survival or tolerance in cardiac xenotransplantation., Objectives: Syrian hamster hearts were transplanted heterotopically into Lewis rats. We compared the survival time and immunopathology of the following five groups: (1) no treatment; (2) DSG (5 mg/kg per day intramuscularly [IM], days -1 to +7) alone; (3) CsA (15 mg/kg per day IM, day 0 to rejection) plus DSG; (4) AdexLacZ (LacZ-adenovirus 1 x 10(9) (PFU intravenously [IV], day -7) plus DSG; and (5) AdexCTLA4IgG (CTLA4IgG-adenovirus 1 x 10(9) PFU IV, day -7) plus DSG., Results: The survival times were: (1) no treatment, 3.7 days; (2) DSG alone, 12.4 days; (3) CyA plus DSG, >100 days; (4) AdexLacZ plus DSG, 11.0 days; and (5) AdexCTLA4IgG plus DSG, 23.6 days. Adenovirus-mediated CTLA4IgG therapy with DSG prolonged survival time significantly compared with DSG alone or AdexLacZ plus DSG, but CTLA4IgG therapy was not as effective as CsA. Immunopathology showed the deposition of C3 and IgM on the endothelium in the AdexCTLA4IgG plus DSG group., Conclusions: We showed that the effectiveness of adenovirus-mediated CTLA4IgG gene therapy in cardiac xenotransplantation in less than that of CsA. Combination therapy with inhibition of the B7/CD28 constimulatory signal and DSG administration might not be sufficient for long-term survival or tolerance in cardiac xenotransplantation.