Prevention of chronic rejection in mouse aortic allografts by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody.
BACKGROUND
In this study, using a murine model of aortic allotransplantation, the role of blockade of signaling through CD28/B7 and CD40/CD40 ligand costimulatory pathways in the evolvement of posttransplant vasculopathy was examined.


METHODS
Aortic allografts were transplanted across C57BL/1OJ (H2b)-->C3H (H2k) strain combinations. Transient or more stable blockade of second signaling was achieved by either a single injection or multiple injections of CTLA4-Ig fusion protein (200 microg/dose i.p.) and/or anti-CD40 ligand (CD40L) monoclonal antibody (250 microg i.m.). At day 30 after transplantation, the grafts were harvested for histopathological and immunohistochemical examination.


RESULTS
Similar to allografts of untreated animals, aortic allografts obtained from recipients treated with either CTLA4-Ig or anti-CD40L monoclonal antibody alone exhibited marked narrowing of the lumen primarily due to concentric intimal thickening caused by proliferation of alpha-smooth muscle actin-positive cells. Contemporaneous treatment, however, with either a single injection or multiple injections of CTLA4-Ig and anti-CD40L monoclonal antibody resulted in marked diminution of intimal thickening. Interestingly, concurrent prolonged inhibition of CD28/B7 and CD40/CD40L pathways resulted in complete abrogation of the development of posttransplant arteriopathy.


CONCLUSIONS
These data suggest that a more stable disruption of signaling through costimulatory pathways may be required to obviate the development of posttransplant vasculopathy.
Sun
H
H
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania 15261, USA.
Subbotin
V
V
Chen
C
C
Aitouche
A
A
Valdivia
L A
LA
Sayegh
M H
MH
Linsley
P S
PS
Fung
J J
JJ
Starzl
T E
TE
Rao
A S
AS
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage*; D001011:Aorta / Q000637:transplantation*; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D002908:Chronic Disease; D004334:Drug Administration Schedule; D006084:Graft Rejection / Q000517:prevention & control*; D018796:Immunoconjugates; D007165:Immunosuppression Therapy / Q000379:methods*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D023201:CD40 Ligand; D000069594:Abatacept