Production and pharmacologic modulation of the granulocyte-associated allergic responses to ovalbumin in murine skin models induced by injecting ovalbumin-specific Th1 or Th2 cells

Because interferon-gamma, interleukin-4, and interleukin-5 have been identi fied at the mRNA and protein levels in the lesional skin of patients with a topic dermatitis, we investigated the roles played by granulocytes as effec tor cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naive splenocytes of antiovalbumi n T cell receptor transgenic BALB/C mice were adoptively transferred with o valbumin into the ear pinnae or air-pouches produced in the back skin of na ive, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin i nduced delayed type ear swelling that peaked at 48 h, whereas that of Th2 r esulted in ear swelling that peaked at a much earlier time, 24 h. Histologi c study of the swollen ear skin and granulocytes recruited into the air-pou ch demonstrated that, although the Th1-induced inflammation caused a neutro phil-predominant infiltrate with few eosinophils, larger numbers of eosinop hils accumulated in the Th2-induced inflammation. Using these murine models , we further evaluated the effects of drugs used for the treatment of atopi c diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neu trophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced infla mmation. In contrast, a leukotriene receptor antagonist, ONO-1078, specific ally suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granuloc ytic effector cells.