CHRONIC BLOCKADE OF CD28-B7-MEDIATED T-CELL COSTIMULATION BY CTLA4IG REDUCES INTIMAL THICKENING IN MHC CLASS-I AND CLASS-II INCOMPATIBLE MOUSE HEART ALLOGRAFTS

Background Chronic rejection develops in MHC class I/II-mismatched mou se allografts with arteriosclerosis and intragraft T-cell activation. Blockade with murine CTLA4Ig was used to study the role of CD28-B7 T-c ell costimulation in this model of vascular thickening. Methods. CBA/C aJ to C57BL/6J vascularized cardiac transplants were treated with muri ne CTLA4Ig delivered as a single dose (250 mu g i.p.) on day 2 or chro nically (100 mu g i.p. on days 0, 2, and 4 and biweekly). Graft surviv al, function, and quantitative vessel analysis were compared with thos e of a reference group treated with anti-CD4 (days 1-4). Results. Day 2 and chronic murine CTLA4Ig treatment prolonged graft survival (mean times and percentage of grafts surviving >75 days) and preserved graft function (measured by palpation scores). However, histology showed th at chronic murine CTLA4Ig grafts had little parenchymal infiltration a nd less prominent vascular occlusion than day 2 murine CTLA4Ig-treated or 4-day anti-CD4-treated grafts. Quantitative analysis showed that t he percentage of diseased vessels and the percentage of luminal occlus ion were high in the day 2 murine CTLA4Ig group (78+/-20% and 41+/-12% , respectively, n=5) and the anti-CD4 group (94+/-9% and 52+/-17%, res pectively, n=9, P=NS), In contrast, the frequency and severity of vess el thickening were significantly reduced in the chronic murine CTLA4Ig group (57+/-13% and 24+/-13%, respectively, n=10, P<0.03), Conclusion . In this model with MHC class I and II disparities, day 2 murine CTLA 4Ig treatment improved survival and function but did not ameliorate va scular thickening. However, ongoing blockade of CH28-B7 costimulation conferred protection against vascular thickening.