The peptide regulatory factors (PRFs), variously termed cytokines, lymphokines, interleukins, colony stimulating factors, interferons, etc., play a key role in the quantitative and qualitative regulation of protective responses—both in initiating immunological and inflammatory responses and in mediating and controlling the effector mechanisms that protect the body against micro-organisms. The process of immunization—involving antigen-presentation, lymphocyte-activation and clonal proliferation—depends on the action of a variety of PRFs. The function of accesssory cells—the dendritic cells, macrophages, etc.—is stimulated by PRFs such as interferon-γ, IL-1, TNF, GM-CSF and IL-4. The activation and expansion of T-lymphocytes requires IL-1, IL-2, IL-4, interferon-y, IL-6 and probably IL-7. Likewise, the activation and expansion of B-lymphocytes is regulated by PRFs such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-7 and interferon-γ. It is likely, although unproven, that PRFs also regulate the differentiation of B-cells to memory cells. Successful vaccination requires the immune system to be primed in such a way that natural challenge with a micro-organism or its products evokes an immune response that has the qualitative and the quantitative characteristics of both the humoral and cellular responses. Antibody class is critically influenced by particular PRFs, e.g. interferon-y regulates IgG2a; IL-4, IgE and IgG,; IL-5 and TGF-β, IgA. PRFs are both produced by and regulate the T-lymphocytes which have key roles in protective responses—either directly, viz. the cytotoxic T-lymphocytes important in protection against certain viruses, or indirectly through the secretion of PRFs that regulate the speed, magnitude and quality of antibody cellular responses. The recruitment and enhanced production and function of granulocytic and phagocytic cells involves a number of T-lymphocyte PRFs including GM-CSF, IL-3, IL-5, IL-4, and IL-6. We do not have a good understanding of the fine-tuning of cellular responses nor of how infection with different pathogens results in different types of inflammatory responses; it is clear, however, that certain cellular responses are due to the action of specific PRFs, e.g. IL-3 induces a mastocytosis and IL-5 an eosinophilia. There is increasing evidence that the relative levels of different PRFs are important determinants of the effectiveness of responses. For example, in Leishmania infections in mice, IL-3 and IL-4 antagonize the protective action of interferon-γ and lead to exacerbation of the disease, and the disease can be ameliorated either by direct administration of interferon-γ or by lowering levels of IL-3 or IL-4 with specific antibodies. Optimal vaccination should ensure that challenge with the specific pathogen stimulates the production of a profile of PRFs that favours the swift development of the type of response that protects against that pathogen. Better understanding of how the production of various PRFs is regulated and how they function in determining the qualitative and quantitative characteristics of immunization and subsequent secondary responses should lead to improved vaccines. For example, it is likely that adjuvants exert their well-known effects on the quality and magnitude of humoral and cellular responses in great part through influencing relative levels of PRFs. The use of PRFs or PRF regulators as adjuvants should be a major step towards more effective and reproducible immunization.
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Mar 1, 1993
E Cahill 
Open Access
