Mechanisms of Tolerance Induced by Donor‐Specific Transfusion and ICOS‐B7h Blockade in a Model of CD4 + T‐Cell‐Mediated Allograft Rejection

The inducible co‐stimulatory molecule (ICOS) has been shown to play a critical role in T‐cell activation and differentiation, and the regulation of alloimmune responses in vivo . Using an MHC class II mismatched model of CD4 + T‐cell‐mediated rejection, we found that treatment of mice with DST and ICOS‐B7h blockade induced long‐term skin allograft survival and donor‐specific transplantation tolerance. ICOS blockade, either during antigen priming or during the effector phase, previously shown to alter the outcome of the immune response, had a similar effect on graft survival. DST and anti‐B7h mAb reduced the frequency of IFN‐γ‐producing allospecific cells but did not produce deviation to a T H 2 phenotype. In an adoptive transfer model using ABM TCR transgenic mice directly reactive to I‐A bm12 , DST and anti‐B7h mAb reduced the number of allospecific CD4 + T cells and increased CD4 + T‐cell apoptosis. These data demonstrate that DST and anti‐B7h mAb induces transplantation tolerance to MHC class II mismatched skin grafts by a reduction of the alloreactive clone size that is, at least in part, dependent on apoptosis of host alloantigen‐specific CD4 + T cells.