The development of effective vaccine adjuvants employing natural regulators of T-cell lymphokine production in vivo.

Steroid hormones are important regulators of gene function in vivo. A number of naturally occurring species of steroid hormones are able to qualitatively and quantitatively influence the production of lymphokines by activated T cells in vitro. Similar mechanisms are probably also occurring naturally in vivo and could explain why mucosal and nonmucosal lymphoid organs harbor T cells having unique potentials for lymphokine production. It was established that the topical application of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to normal mice changed the pattern of lymphokines produced by activated T cells isolated from the draining peripheral lymph nodes. The hormone-treated T cells produced a pattern of lymphokines similar to that normally found in Peyer's patches. Subcutaneous vaccination with a protein antigen, in a site afferent to 1,25(OH)2D3-manipulated lymph nodes, resulted in an enhanced serum antibody response and was uniquely capable of also stimulating a common mucosal immune response to the antigen as well. Common mucosal immunity was confirmed by demonstrating the presence of antigen-specific IgA and IgG responses in a number of mucosal secretions and by further establishing that antibody-secreting plasma cells had migrated to the lungs and small intestines of the hormone-treated and vaccinated animals. Additional experiments established that common mucosal immunity could also be induced in aged animals as long as the immune system of the vaccinated animals was functioning normally. This was accomplished by providing the aged animals with a dietary supplement of dehydroepiandrosterone sulfate (DHEAS). Previous studies by us have documented that aged animals provided with replacement levels of DHEAS, a natural steroid hormone whose endogenous production declines with advancing age, are able to mount normal systemic humoral and cellular immune response following subcutaneous vaccination with a variety of protein and polysaccharide antigens. The combination of supplemental DHEAS therapy with topical 1,25(OH)2D3 treatment at the time of vaccination provided the conditions needed to generate mucosal and systemic immune responses to inactivated influenza virus antigen by old animals.