Abstract
O461 Aims: Blockade of the CD40-CD40L pathway results in long-term allograft survival but does not prevent chronic rejection. Therefore new immunotherapies are needed to obtain tolerance. ICOS and its receptor, B7RP-1, are members of the CD28-B7 families which play an important role in T cell activation and survival. Methods: We used an adenovirus coding for CD40Ig (which blocks CD40-CD40L interactions) in a rat heart allograft transplantation model. We analyzed the effect of co-treatment with an anti-ICOS MAb and CD40Ig on chronic rejection. Results: CD40Ig and anti-ICOS treatment led to indefinite graft survival in all recipients (>120 days). Treatment with anti-ICOS resulted in a modest but significant prolongation of allograft survival (17±1.5 vs 7.6±1.6, p=0.002, n=4). Analysis of chronic rejection lesions at day 120 in the CD40Ig+anti-ICOS group (n=7) vs. the CD40Ig group (n=17) showed that the percentage of vessels occluded (15.2±6.6 vs. 33.7±4.4, p=0.017), degree of vessel occlusion (1.1±0.5 vs. 2.4±0.2, p=0.007) and vessel lesions (1±0.3 vs. 2.3±0.1, p<0.001) but not fibrosis were significantly lower. Importantly, 4 of the 7 CD40Ig+anti-ICOS-treated recipients showed complete absence of chronic rejection lesions whereas all CD40Ig-treated recipients showed signs of chronic rejection. The CD40Ig+anti-ICOS group showed decreased graft infiltration by TCRαβ+, CD4+ and CD8α+ cells as well as macrophages and mast cells. Recipients in the CD40Ig+anti-ICOS group displayed significantly inhibited anti-donor CTL activity. Alloantigenic proliferative responses of splenocytes in the CD40Ig+anti-ICOS group were strongly inhibited and were reversed by IL-2. CD40Ig treatment strongly but incompletely inhibited total IgG, Th2 and Th1-dependant alloantibody production. The residual total IgG and Th1 but not Th2 alloantibody were significantly reduced in the sera of recipients of CD40Ig+anti-ICOS treated allografts at day 120, suggesting an inhibition of Th1 responses. Conclusions: These data indicate that the chronic rejection mechanisms that are CD40-CD40L-independent are ICOS/B7RP-1-dependent. Operational tolerance can be obtained by simultaneous blockade of both costimulatory pathways.
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