AbstractSeveral in vitro studies have shown that murine interleukin‐5 (mIL‐5) enhances IgA production by activated mucosal B cells. To date, however, there is no evidence that this factor significantly up‐regulates mucosal IgA responses in vivo. Here, we show that expression of the gene for mIL‐5 in a recombinant vaccinia virus vector markedly increases IgA responses to co‐expressed heterologous antigen in the lungs of mice given intranasal inocula of the virus. The elevated local IgA responses to vectors expressing mIL‐5 peaked at a fourfold higher level than those elicited by control virus at 14 days after infection and were sustained for at least 4 weeks. Increased IgA responses were abrogated in mice treated with monoclonal antibody against mIL‐5 and were not detected in systemic lymphoid tissue. No enhancement of specific IgG levels was found either locally or systemically. Our results indicate that mIL‐5 selectively enhances the development of mucosal IgA responses in vivo and suggest that expression of this factor in mucosal vaccine vectors may stimulate local immune reactivity.