Many vaccines, particularly subunit vaccines (e.g., recombinant hepatitis B and tetanus toxoid), contain adjuvants that help to increase the response rates to vaccines and facilitate the use of fewer and smaller doses (Coffman et al., 2010). Currently, two adjuvants (alum as aluminum phosphate or aluminum hydroxide, and ASO4, which is comprised of mono-phosphoryl lipid A and alum) are in vaccines licensed for use in the United States. Although the exact mechanism of action of many adjuvants is not completely understood, it is hypothesized that alum delays systemic absorption of injected antigens, resulting in antigen retention in particulate form and in high concentration at the site of local injection (Tritto et al., 2009). This in turn results in prolonged exposure of the cells of the innate immune system to antigen (Tritto et al., 2009). Furthermore, alum may directly activate cells of the innate immune system through its effect on local inflammasome complexes (Coffman et al., 2010) leading to the release of inflammatory mediators and enhancement of the immune response as described above. The review by Coffman et al. (2010) provides a detailed description of the mechanism(s) of action of clinically approved adjuvants including alum and ASO4.

IMMUNE-MEDIATED MECHANISMS

Several immune-mediated mechanisms have been hypothesized to be involved in the pathogenesis of tissue damage or clinical disease related to natural infection or immunizations. A brief description of some of these mechanisms follows.

Effector Functions of T Cells

T cells are the subset of lymphocytes that develop in the thymus. They are further delineated by the expression of cell surface markers and the production of inflammatory and immunoregulatory mediators. Two T cell subsets, CD8+ and CD4+ T cells, are activated via recognition of peptides derived from antigen. For activation of T cells to occur, the peptides are bound to major histocompatibility complexes (MHCs) expressed on the surface of specialized white blood cells called antigen-presenting cells. T cells have various functions in the immune response.

CD8+ T cells are activated in response to antigens that gain access to the cytosol of cells. These antigens are broken down into peptides. The peptides are presented to CD8+ T cells after being bound to class I MHC molecules. Class I MHC molecules are expressed on nearly all nucleated cells (Harty et al., 2000). CD8+ T cells express a T cell receptor (TCR) that binds peptide-class I MHC complexes. CD8+ T cells that express different TCRs allow for recognition of many different antigens. The binding of



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