IMPAIRED MUCOSAL IMMUNE-RESPONSES IN INTERLEUKIN 4-TARGETED MICE

Interleukin 4-targeted (IL-4-/-) mice are defective in T helper (Th)2 cytokine production as determined after nematode infection. As Th2 cel ls appear to be selectively induced by oral immunization we investigat ed the ability of IL-4-/- mice to respond to perorally administered an tigen. We found that IL-4-/- mice failed to respond to soluble protein antigens given perorally together with cholera toxin (CT) as a mucosa l adjuvant. In contrast to wild-type mice no or poor anti-keyhole limp et hemocyanin (KLH) or anti-ovalbumin (OVA)B cell responses were obser ved in gut lamina propria, spleen, or serum of IL-4-/- mice after oral immunization. In addition, mucosal immunization failed to stimulate a ntigen-specific T cell responses in these mice. The lack of responsive ness was specific for mucosal administration of antigen and was not se en after intravenous injections with antigen and CT-adjuvant. The syst emic adjuvant effect of CT was not impaired in IL-4-/- mice as evidenc ed by the strong enhancement of anti-KLH responses after intravenous i mmunization with KLH plus CT as opposed to KLH alone. However, CT as a n immunogen, in contrast to KLH or OVA, stimulated significant mucosal and systemic immune responses in IL-4-/- mice after oral, immunizatio n. Both serum and intestinal IgA anti-CT antibodies were demonstrable in IL-4-/- mice as well as in wild-type mice. Total IgA levels in gut lavage and in serum of immunized IL-4-/- mice were of similar magnitud e as in wild-type mice, suggesting that the ability of naive B cells t o undergo isotype switch-differentiation from IgM to IgA in IL-4-/- mi ce did not appear to be impaired. Immunohistochemical analysis of Peye r's patches demonstrated a complete inability to form germinal centers in IL-4-/- mice in contrast to wild-type mice. Our data suggest that IL-4-/- mice are unable to respond to oral/mucosal immunization due to a failure to stimulate antigen-specific cells required to induce germ inal center reactions in the Peyer's patches. Our findings demonstrate that IL-4 and probably functional Th2 cells are required for inductio n of gut mucosal antibody responses.