CHRONIC BLOCKADE OF CD28-B7-MEDIATED T-CELL COSTIMULATION BY CTLA4Ig REDUCES INTIMAL THICKENING IN MHC CLASS I AND II INCOMPATIBLE MOUSE HEART ALLOGRAFTS1,2

Abstract

Chronic rejection develops in MHC class I/II-mismatched mouse allografts with arteriosclerosis and intragraft T-cell activation. Blockade with murine CTLA4Ig was used to study the role of CD28-B7 T-cell costimulation in this model of vascular thickening. CBA/CaJ to C57BL/6J vascularized cardiac transplants were treated with murine CTLA4Ig delivered as a single dose (250 microg i.p.) on day 2 or chronically (100 microg i.p. on days 0, 2, and 4 and biweekly). Graft survival, function, and quantitative vessel analysis were compared with those of a reference group treated with anti-CD4 (days 1-4). 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 that chronic murine CTLA4Ig grafts had little parenchymal infiltration and less prominent vascular occlusion than day 2 murine CTLA4Ig-treated or 4-day anti-CD4-treated grafts. Quantitative analysis showed that the percentage of diseased vessels and the percentage of luminal occlusion 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%, respectively, n=9, P=NS). In contrast, the frequency and severity of vessel thickening were significantly reduced in the chronic murine CTLA4Ig group (57+/-13% and 24+/-13%, respectively, n=10, P<0.03). In this model with MHC class I and II disparities, day 2 murine CTLA4Ig treatment improved survival and function but did not ameliorate vascular thickening. However, ongoing blockade of CD28-B7 costimulation conferred protection against vascular thickening.