The effects of HLA mismatching and immunosuppressive therapy on early rejection outcome in pediatric heart transplant recipients.
BACKGROUND
Although HLA-DR antigen mismatching between heart transplant recipients and donors has been associated with increased early allograft rejection in adult patients treated with cyclosporine, little information exists in the pediatric age group. In this study we examined retrospectively the effects of HLA mismatching and immunosuppression choice, cyclosporine versus tacrolimus on early rejection outcome in pediatric heart transplant recipients.


METHODS
Between 1992 and 1997, 38 patients (ages 10 days to 18 years) underwent 40 heart transplantations. All recipients were typed prospectively and donors retrospectively by use of serologic microcytotoxicity testing for HLA-A and HLA-B antigens and by a polymerase chain reaction technique for HLA-DR antigens. All heart transplant recipients received induction immunosuppression with methylprednisolone and maintenance prednisone, and 38 received OKT3. The first 25 heart transplant recipients received cyclosporine and azathioprine, and the last 15 were given tacrolimus. Clinical courses, HLA mismatching, and biopsy results for the first year after heart transplantation were reviewed and compared between treatment groups.


RESULTS
Mean age, donor/recipient weight ratios, and biopsies/patient were similar between treatment groups. Five deaths occurred among cyclosporine-treated patients and none among tacrolimus-treated patients during the study period. HLA mismatching was similar between groups, with 94% of patients having 1 or 2 HLA-A mismatches and 96% having 1 or 2 HLA-B and -DR mismatches. Both International Society for Heart and Lung Transplantation grade 2 and grade 3 or 4 rejections were significantly increased in biopsies from cyclosporine-treated patients (P < .05). Significantly increased grade 3 or 4 rejection was present in patients treated with cyclosporine who had two DR mismatches versus those with one DR mismatch (3.0+/-1.6 vs 1.4+/-0.8; P < .05); no statistical significance between patients treated with tacrolimus with 1 vs 2 DR mismatches was noted. Patients treated with tacrolimus who had 2 DR mismatches had fewer grade 3 or 4 rejection episodes/patient than either patients treated with cyclosporine who had one DR mismatch (0.6+/-0.4 vs 1.4+/-0.8, P = .03) or those treated with cyclosporine who had two DR mismatches (0.6+/-0.4 vs 3.0+/-1.6, P = .01). Grade 3 or 4 rejection episodes/patient were not affected by HLA-A or B mismatching, and grade 2 rejection was not affected by mismatching at any of the loci.


CONCLUSIONS
Although mismatching of HLA-A and -B antigens did not affect frequency of early cellular rejection, the presence of 2 HLA-DR loci mismatches increased the risk of high-grade rejection in pediatric heart transplant recipients treated with cyclosporine. The potent effects of tacrolimus-based immunosuppression mitigated the impact of HLA-DR mismatching, because patients treated with tacrolimus who had 2 DR mismatches had less rejection than even patients treated with cyclosporine who had one DR mismatch and seemed to be at no greater risk for rejection than patients treated with tacrolimus who had 1 DR mismatch.
Herzberg
G Z
GZ
Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Rossi
A F
AF
Courtney
M
M
Gelb
B D
BD
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015234:HLA-A Antigens / Q000032:analysis; D015235:HLA-B Antigens / Q000032:analysis; D006684:HLA-DR Antigens / Q000032:analysis; D016027:Heart Transplantation / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D009206:Myocardium / Q000473:pathology; D016559:Tacrolimus / Q000627:therapeutic use
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus