Strategies to Induce Marked Prolongation of Secondary Skin Allograft Survival in Alloantigen‐Primed Mice

Alloreactive memory T cells mediate accelerated rejection. We investigated the effect of polyclonal anti‐T‐cell antibody (ALS) and rapamycin (RAPA) on skin allograft survival in naïve or alloantigen‐primed mice. ALS prolonged graft survival in both naïve and alloantigen‐primed mice. T‐cell depletion by ALS was associated with increased CD4 + CD44 hi OX40 + and CD8 + CD44 hi CD122 + memory T cells. Addition of RAPA to ALS extended graft survival in naïve mice, but had no effect on secondary allograft survival in alloantigen‐primed mice. In adoptive transfer experiments, RAPA inhibited alloantigen‐stimulated proliferation and allograft rejection by naïve T cells. In contrast, alloantigen‐primed memory T cells, particularly CD4 + CD44 hi OX40 + and CD8 + CD44 hi CD122 + T cells, were resistant to RAPA in response to alloantigen and mediated accelerated rejection in the presence of RAPA. Resistance to RAPA by alloantigen‐primed mice was overcome by the use of high‐dose ALS, which achieved marked prolongation of secondary skin allograft survival (>100 days). Inhibition of CD122 + T cells and/or OX40/OX40L costimulation blockade, combined with low‐dose ALS and RAPA, was also effective. These results demonstrate that tolerance may be achieved in allosensitized individuals by T‐cell depletion‐ and RAPA‐based strategies employing high‐dose ALS or targeting CD122 + CD8 + T cells and/or the OX40/OX40L costimulatory pathway.