Anti-LFA-1 monotherapy prevents neointimal formation in a murine model of transplant intimal hyperplasia.
BACKGROUND
Cardiac allograft vasculopathy (CAV) is the pre-eminent cause of late cardiac allograft failure. It is characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). To date, blockade of the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) has been shown to be effective in preventing TIH in experimental models of transplantation, but only when combined with other immunosuppressants. In this study we explored the impact of monotherapy against LFA-1 in a carotid artery allograft model of TIH.


METHODS
B10A(2R) (H-2(h2)) mice were used as donors and C57BL/6 (H-2(b)) mice used as recipients. The recipients were treated with a monoclonal antibody against LFA-1alpha (M17/4) or isotype-matched control immunoglobulin. Grafts were harvested after 35 days and analyzed by histomorphometry and immunohistochemistry. Blood samples were taken and analyzed by differential cell count and alloantibody levels.


RESULTS
We found that treatment with M17/4 resulted in a significant reduction in TIH compared with controls. Immunostaining revealed that LFA-1alpha blockade inhibited CD45+ leukocyte infiltration, prevented intimal smooth muscle cell (SMC) proliferation, and preserved the medial SMC population. Finally, we demonstrated a reduction in the serum alloantibody titer in the group treated with anti-LFA-1alpha when compared with controls.


CONCLUSIONS
We have demonstrated for the first time that LFA-1alpha blockade on its own can prevent development of TIH in an experimental model. The concept of modulating LFA-1alpha-mediated leukocyte migration and T-cell activation may therefore be of relevance to clinical cardiac transplantation and, as such, represents a potential target for therapeutic intervention against clinical CAV.
Soleimani
Behzad
B
Department of Cardiac Surgery, National Heart and Lung Institute, London, UK. b.soleimani@imperial.ac.uk
Wieczorek
Grazyna
G
Katopodis
Andreas
A
Zenke
Gerhard
G
George
Andrew J T
AJ
Hornick
Philip I
PI
Weitz-Schmidt
Gabriele
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002339:Carotid Arteries / Q000473:pathology / Q000637:transplantation*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006965:Hyperplasia / Q000209:etiology / Q000517:prevention & control; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016378:Tissue Transplantation / Q000009:adverse effects / Q000473:pathology; D017539:Tunica Intima / Q000473:pathology*
D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1