In conclusion, these findings from in vitro and in vivo studies demonstrate that DP IV activity associated with CD26 plays an important role in the activation of autoreactive T cells. Moreover, inhibition of both DP IV/CD26 and APN/CD13 activity in vitro and in vivo provides a new approach to modulate T cell functions and tissue-specific autoimmunity in the CNS. These results may have important implications for the treatment of human diseases with a putative autoimmune pathogenesis. At present, major research efforts are directed at the investigation of DP IV/CD26 and APN/CD13 as potentially powerful and safe pharmacological targets. Our preliminary data raise the possibility that simultaneous inhibition of DP IV/CD26 and APN/CD13 may be advantageous over targeting a single ectopeptidase, and support the development of inhibitors with dual specificities for both ectopeptidases.