Transplant acceptance following anti-CD4 versus anti-CD40L therapy: Evidence for differential maintenance of graft-reactive T cells

Inductive therapy with anti-CD4 or anti-CD40L monoclonal antibodies (mAb) leads to long-term allograft acceptance but the immune parameters responsible for graft maintenance are not well understood. This study employed an adoptive transfer system in which cells from mice bearing long-term cardiac allografts following inductive anti-CD4 or anti-CD40L therapy were transferred into severe combined immunodeficiency (SCID) allograft recipients. SCID recipients of cells from anti-CD4-treated mice (anti-CD4 cells) did not reject allografts while those receiving cells from anti-CD40L-treated mice (anti-CD40L cells) did reject allografts. Carboxyfluorescein succinimidyl ester (CFSE) labeling of transferred cells revealed that this difference was not associated with differential proliferative capacities of these cells in SCID recipients. Like cells from naive mice, anti-CD40L cells mounted a Th1 response following transfer while anti-CD4 cells mounted a dominant Th2 response. Early (day 10) T-cell priming was detectable in both groups of primary allograft recipients but persisted to day 30 only in recipients treated with anti-CD4 mAb. Thus, anti-CD40L therapy appears to result in graft-reactive T cells with a naive phenotype while anti-CD4 therapy allows progression to an altered state of differentiation. Additional data herein support the notion that anti-CD40L mAb targets activated, but not memory, cells for removal or functional silencing.