Vitamin A deficiency increases the risk of childhood mortality, presumably due to poor immune responses to infectious diseases. Using well controlled animal models, we have shown that the antibody response to immunization is particularly low against T cell-dependent (TD) and T cell-independent type 2 antigens. Nonetheless, vitamin A-deficient animals can produce strong antibody responses to these antigens, even above normal levels, when treated with agents including retinoids, lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, or the double-stranded RNA, poly(I:C), a known inducer of interferons (IFNs). Other cell biological and clinical research supports a positive synergistic interaction of retinoids and cytokines-including TNF and IFNs-in inhibiting tumor cell growth. Thus, we propose to investigate retinoid-cytokine interactions in the immune system, utilizing vitamin A-deficient, control, retinoid-repleted, and transgenic mice as models. Experiments are designed to understand how TNF, hype I and type II IFNs, and cytokine inducers retinoids, monophosphoryl lipid A (MPL), or poly(I:C)-Iysine carboxymethylcellulose] amplify antigen-specific responses to TD and type 2 antigens (exemplified by tetanus toxoid and pneumococcal polysaccharide, respectively, in our studies). We will test the hypothesis that these agents increase the expression of interleukin (IL)-12, a cytokine with broad immunoregulatory activity; the IL-2 receptor, an immediate early gene; and STAT1, a member of the Signal Transducers and Activators of Transcription family of post- receptor factors that transduce signaling for type I and type II IFNs. By investigating the quantitative and qualitative characteristics of antigen-specific and non-specific immune responses following treatment with retinoids and adjuvants, we hope to improve the mechanistic understanding of retinoid-cytokine interactions, and to elucidate the potential of nutritional and adjuvant strategies to enhance immunity in immunocompromised hosts.
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