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It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis rats. Results presented below demonstrate that amounts of pretransplant anti-CD4 sufficient to allow allograft tolerance in low responder strains (5 mg/kg x 4 days) did not prevent the acute rejection of ACI heart allografts in high responder Lewis recipients. Higher doses of pretransplant anti-CD4 (10 mg/kg, 15 mg/kg, and 20 mg/kg) given alone could delay but not prevent allograft rejection. Pretransplant anti-CD4 combined with anti-CD8, thymectomy, and total lymphoid irradiation all failed to produce tolerance to ACI heart allografts. However, a regimen of anti-CD4 combined with CTLA4Ig allowed indefinite survival of ACI heart allografts (mean survival time, > 100 day). Second-donor matched heart grafts were permanently accepted, and third-party heart grafts were permanently accepted, and third-party heart allografts were rejected by the tolerant recipients. These results suggest a new combination therapeutic strategy for clinical transplantation.
Before the use of cyclosporine as the major component for immunosuppression after cardiac transplantation, rejection was accompanied by catastrophic hemodynamic decompensation. However, the hemodynamic changes that occur during rejection after cardiac transplantation in patients treated with cyclosporine have not been clearly described. Between July 1986 and October 1989, 89 adults underwent orthotopic heart transplantation at the University of Michigan Medical Center. All patients received triple-drug therapy immunosuppression consisting of steroids, cyclosporine, and azathioprine. Cardiac hemodynamics were measured and correlated with the histologic assessment of rejection. There have been ten deaths among these 89 patients for an overall survival of 89%. There were no deaths from rejection. One hundred fifty-three of the biopsy specimens were read as grade 0, 31 were grade 1, 75 were grade 2, 103 were grade 3, and 9 patients had grade 4 biopsy specimens. No hemodynamic differences were noted in patients with increasing grade of rejection. Five patients (5/9, 55%) with severe rejection (grade 4) had symptoms of congestive heart failure at the time of biopsy. These symptomatic grade 4 patients differed from asymptomatic grade 4 patients only in cardiac output (2.9 versus 5.2 L/min). Overall hemodynamic decompensation was not evident as rejection grade increased. Routine serial endomyocardial biopsies remain the procedure of choice in the diagnosis of rejection in the asymptomatic patient after cardiac transplantation as hemodynamics do not predict degree of rejection.