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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Thoracic and Cardiovascular Surgery, University of Saarland, Saarland, Germany. reneschramm@live.com
René
R
Schramm
Rudolph
R
Schmits
Hans-Joachim
HJ
Schäfers
Michael D
MD
Menger
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000517:prevention & control*; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology*; D014184:Transplantation, Homologous
D000924:Anticholesteremic Agents; D018106:CD28 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D019821:Simvastatin