Relation of HLA antibodies and graft atherosclerosis in human cardiac allograft recipients

Although cyclosporine has helped make heart transplantation a clinical reality, long-term survival remains limited by rejection and graft atherosclerosis. We have previously demonstrated the development of alloreactive lymphocytotoxic antibodies in baboon recipients of heterotopic heart transplants despite cyclosporine administration. The hypothesis of the present study is that cyclosporine-treated human heart transplant recipients are also capable of generating strong humoral immune responses that might adversely affect clinical outcome. Serial serum specimens from 240 heart transplant recipients were tested against a reference panel of 70 cells for anti-HLA lymphocytotoxic antibodies. Patients with serum panel reactive antibody levels greater than 10% were considered antibody producers, whereas those with serum panel reactive antibody levels less than 10% were considered nonproducers. To establish the time course of post-transplantation sensitization, we have tested anti-HLA antibodies in sequential sera at 3- month intervals after transplantation. The 4-year actuarial survival rate of those patients whose panel reactive antibody levels were greater than 10% during the first 6 months after transplantation was 70%, whereas the survival rate of patients whose levels were less than 10% during this time was 93%. The results were significantly different (p < 0.01). Further heterogeneity among the patients was demonstrated by differential analysis of survival in patients who showed (1) panel reactive antibody levels less than 10% in any of the sera obtained during the first year after transplantation, (2) panel reactive antibody levels greater than 10% in sera obtained during the first 6 months but not thereafter, and (3) panel reactive antibody levels greater than 10% throughout the first year after transplantation. The 3-year survival rate was 100% in patients whose panel reactive antibody levels were less than 10% during the entire period, 91% in patients with panel reactive antibody levels greater than 10% only in the first semester, and 70% in patients with panel reactive antibody levels greater than 10% throughout the first 12 months after transplantation. This indicates that patients with levels greater than 10% whose antibody levels became less than 10% had a better prognosis than those patients who continued with higher levels (p < 0.03). To determine the prognostic significance of the anti-HLA antibody production, we calculated the actuarial survival rate of allografts in patients who produced antibodies early (during the first 6 months) and late (after the first 6 months) after transplantation. Patients with early onset of antibody production showed a significantly lower (p < 0.03) 4-year survival rate (69%) than patients who formed antibodies after 6 months (91%).