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.
Schramm
René
R
Department of Thoracic and Cardiovascular Surgery, University of Saarland, Saarland, Germany. reneschramm@live.com
Schmits
Rudolph
R
Schäfers
Hans-Joachim
HJ
Menger
Michael D
MD
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