Compositions and methods disclosed herein capitalize on the discovery that rejection of a tissue graft can be inhibited using a CD40:CD154 binding interrupter, either alone or in combination with another immunomodulator or immunosuppressor. An advantageous, synergistic combination includes a CD40:CD154 binding interrupter and a CD28 signaling interrupter. An exemplary CD40:CD154 binding interrupter is an anti-CD154 monoclonal antibody, such as an antibody having the antigen-specific binding characteristics of the 5c8 monoclonal antibody. An exemplary CD28 signaling interrupter is a CTLA4-Ig fusion protein. The disclosed compositions and methods unexpectedly can be used to prolong survival of grafted tissue in a recipient host, to reverse acute graft rejection, and to attenuate immunological consequences of the failure of grafted tissue.