Suppression of murine cardiac allograft arteriopathy by long-term blockade of CD40-CD154 interactions.
BACKGROUND
The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure.


RESULTS
A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days -1, 1, and 3; long-term blockade consisted of MR1 given on days -1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43+/-7% and 50+/-12%, respectively (P=NS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19+/-3% (P<0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control (P<0.05).


CONCLUSIONS
These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.
Wang
Catherine Y
CY
Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Mazer
Sean P
SP
Minamoto
Kanji
K
Takuma
Shin
S
Homma
Shunichi
S
Yellin
Michael
M
Chess
Leonard
L
Fard
Ali
A
Kalled
Susan L
SL
Oz
Mehmet C
MC
Pinsky
David J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000276:immunology; D002465:Cell Movement; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation; D007150:Immunohistochemistry; D007700:Kinetics; D008297:Male; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology; D014463:Ultrasonography
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D015815:Cell Adhesion Molecules; D023201:CD40 Ligand