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 allotranspla ntation, the role of blockade of signaling through CD28/B7 and CD40/CD 40 ligand costimulatory pathways in the evolvement of posttransplant v asculopathy was examined, Methods. Aortic allografts were transplanted across C57BL/10J (H2(b))-->C3H (H2(k)) 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 (20 0 mu g/dose i.p.) and/or anti-CD40 ligand (CD40L) monoclonal antibody (250 mu g i.m.), At day 30 after transplantation, the grafts were harv ested for histopathological and immunohistochemical examination, Resul ts, Similar to allografts of untreated animals, aortic allografts obta ined from recipients treated with either CTLA4-Ig or anti-CD40L monocl onal 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 an d anti-CD40L monoclonal antibody resulted in marked diminution of inti mal thickening. Interestingly, concurrent prolonged inhibition of CD28 /B7 and CD40/CD40L pathways resulted in complete abrogation of the dev elopment of posttransplant arteriopathy, Conclusion, These data sugges t that a more stable disruption of signaling through costimulatory pat hways may be required to obviate the development of posttransplant vas culopathy.