The B7-CD28 pathway is one of the foremost costimulatory pathways involved in T-cell activation. Recently, a number of additional costimulatory pathways have been described and preliminary data suggest that they play important roles in alloimmunity. However, the interactions between these different pathways are not well understood. We studied the effect of targeting ICOS ligand, B7RP1, in a rat cardiac transplant model, with and without concomitant blockade of the B7 pathway using CTLA4lg. In a fully mismatched WF to LEW vascularized cardiac allograft model, without therapy, grafts were acutely rejected (MST 10.8±1.6 days). Early (day of transplant) B7RP1 blockade with ICOSlg alone had little effect on graft survival and rather than being additive with B7 blockade, ICOSlg abrogated the prolonged graft survival induced by CTLA4lg treatment. By contrast, delayed (day 2 post-transplant) blockade of B7RP1 did not have such an effect. These findings were not related to cytokine deviation but may be in part related to the pattern of down-regulation of B7.2 expression following early B7RP1 blockade. This is the first report describing the complex interactions between ICOS-B7RP1 and B7-CD28 costimulatory pathways in alloimmunity in vivo.
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