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Many clinical studies or case reports have focused on the clinical consequences of immunoenhancement or immune dysregulation mediated by therapeutic cytokines. Flu-like reactions, and the facilitation or exacerbation of inflammatory diseases, are the main consequences of immunoenhancement. Flu-like symptoms commonly are observed in patients treated with interferons, interleukin (IL)-l, IL-2, IL-3, or tumor necrosis factora. They typically consist of fever and chills, malaise, tachycardia, arthralgias, and myalgias that develop within a few hours after administration. The mechanism is not clearly understood but probably involves the acute release of fever-promoting factors in the hypothalamus. Because various cytokines are directly or indirectly involved in the pathogenesis of immune-mediated inflammatory disorders and autoimmune diseases, it is not surprising that such disorders develop after the administration of pharmacological doses of these cytokines. Another adverse consequence is the development of cytokine-specific antibodies in the sera of treated patients. [ABSTRACT FROM AUTHOR]

The goal of cancer immunotherapy is to induce effective immune responses to malignant tumors. Immunostimulatory cytokines can promote antitumor immunity by augmenting immune responses to cancer cells and by reversing anergy and/or tolerance of immune effector cells. The clinical development of cytokines for cancer therapy has been hampered by difficulty in determining the optimal dose and schedule of these molecules. The successful development of cytokine-based therapy requires assays that can measure appropriate surrogate endpoints for the induction of effective antitumor immunity in vivo. Several in vitro assays that have been useful for monitoring the immunological effects of cytokine therapy in humans will be discussed in this chapter. Each technique has advantages and limitations and no single assay has been found to reliably predict antitumor efficacy during clinical immunotherapy. [ABSTRACT FROM AUTHOR]

The expression of cytochrome P450 and P-glycoprotein is altered during the operation of host defense mechanisms. The basis for this interaction is predominantly through cytokine-mediated pathways. Most of the major cytokines, including interleukin (IL)-lα, IL-lβ, IL-2β, IL-6, tumor necrosis factor-α, inteferon-α, inteferon-γ, and transforming growth factor-β, are known to downregulate the major forms of cytochrome P450 and P-glycoprotein. In most cases individual cytochrome P450 forms are downregulated at the level of gene transcription, with a resulting decrease in the corresponding messenger ribonucleic acid, protein, and enzyme activity. The cytokine-mediated loss in drug metabolism is channeled predominantly through the modification of specific transcription factors. Similar pathways appear to alter the expression of P-glycoprotein. In clinical medicine, there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component and the production of cytokines. The direct administration of cytokines to humans depresses the levels of several cytochrome P450-mediated pathways. The production of cytokines in humans often results in altered drug responses and increased toxicities, which has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs is severely compromised. Changes in drug-handling capacity during inflammation/infection will continue to be one of the many factors that complicate therapeutics. [ABSTRACT FROM AUTHOR]

A key component for the success of any therapeutic cytokine is the degree of immunogenicity mediated by the cytokine. There are many factors that can contribute to a cytokine being immunogenic, such as aggregation. The understanding of cytokine immunogenicity requires a thorough knowledge of the antibody testing that was performed. Some of the methods used to test for antibodies against cytokines are the enzyme-linked immunosorbent assay, radioimmune precipitation assay, electrochemiluminescence, and surface plasmon resonance platforms. To understand whether an anticytokine antibody can neutralize the biological effect of a cytokine, it is necessary to perform a bioassay. The significance of cytokine immunogenicity can only be understood in the context of antibody testing data coupled with clinical data related to effects on the patient. [ABSTRACT FROM AUTHOR]