Local and systemic effects of co‐stimulatory blockade using cytotoxic T lymphocyte antigen‐4‐immunoglobulin in dinitrofluorobenzene‐ and oxazolone‐induced contact hypersensitivity in mice

Summary Cytotoxic T lymphocyte‐associated antigen‐4 ( CTLA ‐4)‐immunoglobulin ( Ig ) has immunosuppressive properties both in vivo and in vitro , but much is still unknown about the mechanisms by which CTLA‐4 ‐ Ig exerts its immunosuppressive activities in vivo . The aim of this study was to investigate the effect of CTLA‐4 ‐ Ig in a mouse model of contact hypersensitivity ( CHS ). The inflammatory response in the presence or absence of CTLA‐4 ‐ Ig was evaluated by measuring the increase in ear thickness in sensitized animals after challenge. We observed a dose‐dependent suppression of the ear swelling in both dinitrofluorobenzene ( DNFB )‐ and oxazolone‐induced CHS . The suppressive effect was still present 3 weeks after administration, even in the absence of circulating levels of CTLA‐4 ‐ Ig . It was further shown that CTLA‐4 ‐ Ig inhibits activation of T cells in the draining lymph node after sensitization and affects the maturation level of both dendritic cells and B cells. Furthermore, CTLA‐4 ‐ Ig reduces infiltration of activated CD 8 + T cells into the inflamed ear tissue and suppresses both local and systemic inflammation, as illustrated by reduced expression of cytokines and chemokines in the inflamed ear and a reduced level of acute‐phase proteins in circulation. Finally, our results suggest that CTLA‐4 ‐ Ig has a mainly immunosuppressive effect during the sensitization phase. We conclude that CTLA‐4 ‐ Ig induces long‐term immunosuppression of both DNFB ‐ and oxazolone‐induced inflammation and our data are the first to compare the effect of this compound in both DNFB ‐ and oxazolone‐induced CHS and to show that CTLA‐4 ‐ Ig exerts an immunosuppressive effect on both local and systemic inflammatory mediators which is mediated principally during the sensitization phase.