Rapid dendritic cell activation and resistance to allotolerance induction in anti-CD154-treated mice receiving CD47-deficient donor-specific transfusion

摘要

CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here, we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47^+/+ B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST>150d). Although donor heart survival was improved compared to non-treated (MST=7d) and anti-CD154 alone (MST=15d) controls, the graft survival time was significantly reduced in anti-CD154-treated BALB/c mice that received CD47^+/− (MST=90d) or CD47^−/− B6 DST (MST=42d) compared to those receiving CD47^+/+ B6 DST. Recipient mice treated with anti-CD154 plus CD47^−/− or CD47^+/− DST also showed significantly increased anti-donor, but not anti-3^rd-party, MLR responses compared to those receiving anti-CD154 and CD47^+/+ DST. Furthermore, CD47^−/− DST induced rapid activation of CD11c^hiSIRPα^hiCD8α⁻ DCs via a mechanism independent of donor alloantigens. These results demonstrate that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.