Irinotecan Combined with Co-Stimulatory Molecule Blockade Prolongs Survival of Cardiac Allografts in Alloantigen-Primed Mice: 347

Memory T cells play an important role in graft rejection. In this study, we investigated the potential effect of Irinotecan (CPT-11), a topoisomerase I inhibitor active in the treatment of a variety of solid tumor malignancies, on memory T cells. CPT-11 treatment alone or combined with blocking monoclonal antibodies (mAb) against co-stimulatory molecules (LFA-1 and CD154) was evaluated in the prevention of heart transplant rejection in alloantigen-primed mice. Alloantigen-primed mice were randomly divided into 4 groups of 6 animals each. The control group was given normal saline. The CPT-11 group received CPT-11 (20 mg/kg/d) (i.p.) on days 0-3 post-transplantation. The Ab group received 100 μg anti-LFA-1 mAb+250 μg anti-CD154 mAb (i.p.) on the day of transplantation and 3 more times every alternate day, and the Ab+CPT-11 group received a combined CPT-11 and Ab treatment protocol. Allograft survival nearly doubled in the CPT-11 group and Ab group compared with the control group (5, 6.3 vs. 3 days). A marked prolongation (39.3 days) of graft survival was achieved by the combination protocol compared with the control group (3 days). Five days after transplantation, cardiac allografts, splenic T cells and serum were harvested for analysis. Compared with the control group, the treatment groups showed alleviation of allograft rejection to different extents, with the CPT-11+Ab group showing the most significant changes. Our data suggest that CPT-11 works by reducing the expression of IL-2/IFN-γ and increasing IL-10/TGF-β expression in both peripheral blood and within the grafts. CPT-11 could also inhibit alloresponses of memory T cells, while decreasing the proportion of CD4+ memory T cells in the spleen of the recipients and significantly reducing serum alloantibody levels. Our study highlights an obvious synergistic action of CPT-11 when combined with co-stimulatory molecule blockade in prolonging the survival of cardiac allografts in alloantigen-primed mice.