Influence of gender on allograft rejection in a rat heart transplant model

Background: Clinical studies have reported increased rejection in female heart transplant recipients. Conflicting data exist as to whether rejection is increased with male donors or female donors in these female recipients. Methods: We investigated in this study allograft rejection in four sets of gender combinations with and without immunosuppression with the use of a heterotopic rat heart transplant model: male donor heart to female recipient, female donor heart to female recipient, male donor to male recipient, and female donor to male recipient. To examine the possible effect of androgens as an immunosuppressant, we orchiectomized a group of male recipient rats before transplantation. The rats that were not immunosuppressed were evaluated for length of graft survival (palpation). In the immunosuppressed rats (cyclosporine, 10 mg/kg x 7 days) in each gender combination half of the grafts were evaluated for length of survival (palpation) and half for cellular rejection grade at day 14 (microscopy). Results: When rats that underwent transplantation were not immunosuppressed, no difference in graft survival time was found among the four sets of gender combinations. With immunosuppression, median graft survival time was 23 days in female recipients versus 32 days in male recipients (p < 0.05). Mean cellular rejection grade at day 14 was 2.95 ± 0.7 in female recipients and 0.8 ± 0.4 in male recipients (p < 0.01). No significant difference was found in graft survival time or cellular rejection grade with respect to donor gender. The graft survival times and cellular rejection grades of the male rats undergoing orchiectomy were not different from those of normal male recipients (p = NS). Cyclosporine levels on day 7 in both male and female recipients were high, female levels (1039 ± 411 ng/ml) were less than male levels (2029 ± 379 ng/ml) (p < 0.01). Conclusions: Female recipients of heterotopic rat heart transplants had shorter graft survival time and increased cellular rejection as compared with male recipients. Donor gender had no influence on graft survival or cellular rejection grade. Orchiectomy had no influence on graft survival time or grade of rejection. Results of this model suggest that female recipients may require increased immunosuppression and rejection surveillance, regardless of donor gender.