TAMOXIFEN PROLONGS HEART ALLOGRAFT SURVIVAL IN CYCLOSPORIN TREATED FEMALE MICE

Abstract

525 Introduction: An increased risk of acute rejection in female heart allograft recipients under Cyclosporin A (CsA) immunosuppression has been reported. Although several factors like gender-specific absorption of CsA, recognition of minor antigens and sensitization of female recipients to MHC antigens during pregnancy are discussed as possible causes, the exact mechanisms of gender-specific differences in alloreactivity are not completely understood. Aim of the following study was to identify gender-dependent factors influencing allograft survival in a murine heterotopic heart transplant model. Material and Methods: Hearts of 8-10 week old male (m) or female (f) C57BL/10 (H-2b) donors were placed into the right cervical position of 10-12 week old male or female C3H/He(H-2k) recipients using a standardized cuff-technique. During the first postoperative week recipients were treated with CsA (15 mg/kg/d) i.m., 17β-estradiol (3.2 µg/d) and/or Tamoxifen (400 µg/d). To test for the impact of donor gender on graft survival a total of four donor-recipient pairs were used: m-m, m-f, f-m, f-f. Female recipients were ovarectomized at the age of 6 weeks. Each experimental group consisted of 6 recipients. Rejection was defined as cessation of palpable contractions, expressed as mean survival (days) ± SD. Results: Allograft survival in untreated male and female C3H/He recipients was 8.1±1 and 7.14±1 days, respectively. CsA prolonged survival in male recipients up to 15.2±1.7 vs. 9.16±0.4 days in female recipients(p<0.05). Graft survival was independent of donor gender in female recipients. Graft survival was significantly shortened in male recipients treated with CsA and 17β-estradiol (11.83±0.8 days). Ovarectomy or administration of Tamoxifen prolonged graft survival in female recipients with CsA immunosuppression from 9.16±0.4 to 13.16±1.2 days(p<0.05). In contrast, female recipients after ovarectomy showed only 9.5±0.8 days survival when CsA and estradiol were administered. Tamoxifen was again able to prolong graft survival under these conditions(12.3±0.8 days). CsA whole blood levels were similar in male and female recipients and did not account for the differences seen in graft survival in both groups. Conclusions: CsA significantly prolonges C57BL/10 heart allograft survival in male C3H/He recipients as compared to female hosts (15.2 vs. 9.16 days). 17β-estradiol reduces graft survival in male recipients, whereas ovarectomy prolongs survial in female hosts. For the first time, a beneficial effect of Tamoxifen on graft survival in conjunction with CsA immunosuppression is demonstrated. The impact of female gonadal hormones on alloreactivity is under current investigation.