A novel anti-CD40 antibody prevents activation of alloreactive T cells and prolongs skin allograft survival

Abstract

Abstract Targeting the CD40-CD154 pathway to induce transplantation tolerance has been of interest to transplantation immunologists for over two decades. The efficacy of anti-CD154 antibody (Ab) observed in murine and non-human primate models for preventing allograft rejection and suppressing autoimmunity, generated great interest in the development of this antibody for clinical use. However, clinical trials with anti-CD154 Ab resulted in thromboembolic complications in patients as a result of CD154 expression by human platelets and limited the clinical application. To develop an alternative approach to anti-CD154 Ab, recent efforts have focused on targeting its receptor, CD40. In this study we evaluated the effects of a novel murine antagonistic antibody to CD40 (BI CD40-1) on alloreactive immune responses. Costimulation blockade consisting of donor splenocytes (DST) and BI CD40-1 reduced activation of alloreactive CD8 T cells as shown by inhibition of expansion, decreased cytokine production and decreased killing of allogeneic targets using an in vivo cytotoxicity assay. Moreover DST/BI CD40-1 treatment significantly prolonged skin graft survival in a BALB/c to B6 MHC mismatch model. The efficacy of BI CD40-1 in preventing alloreactive T cell responses was similar to anti-CD154 Ab. These results indicate that anti-CD40 Ab is an attractive candidate for translation to clinical application.