Simvastatin does not prevent acute cardiac allograft rejection in CD28-deficient mice

Heterotopic cardiac transplantation in mice was used to determine whether complementary immunomodulation by statins prevents lymphocyte function-associated antigen (LFA)-1-dependent acute allograft rejection in vivo.

Hearts from BalbC mice were transplanted to the cervical vessels of either C57BL/6, CD11a(-/-), CD28(-/-) or double-deficient animals lacking expression of both LFA-1 and CD28.

Allografts were rejected at days 7.2 +/- 0.7, 9.1 +/- 0.6 and 10.3 +/- 1.2 in C57BL/6, CD11a(-/-) and CD28(-/-) recipients, respectively. In contrast, mean allograft survival time in double-deficient animals was 27.2 +/- 2.9 days, indicating that acute allograft rejection in CD28(-/-) recipients was critically dependent on LFA-1 function. Allograft rejection was not delayed in CD28(-/-) recipients treated daily with 1 or 40 mg/kg simvastatin, graft survival was 9.6 +/- 0.2 and 10.3 +/- 0.3 days in these animals. Histology revealed that all rejected allografts uniformly presented with high-grade parenchymal rejection.

Targeting of both LFA-1 and CD28 may provide efficient inhibition of co-stimulation and thus prolong experimental cardiac allograft survival. Simvastatin is not effective to blunt LFA-1-dependent acute cardiac allograft rejection in CD28(-/-) mice. Thus, pharmacological antagonism of LFA-1 function by oral treatment with statin compounds has to be considered an unsatisfactory means to improve the outcome after cardiac transplantation.