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Biologic Response Modifiers


Cytokines (polypeptides released mainly by immune cells) regulate cell growth and differentiation, apoptosis, inflammation, immunity, and repair and are important in the pathogenesis and treatment of disease. The complexities of cytokine nomenclature have been addressed by the World Health Organization, which provides a nomenclature system that includes cytokines of veterinary interest. Cytokines with application in companion animal medicine include interferons (IFN), interleukins (IL), and hematopoietic growth factors.

Most cytokines are secreted by a variety of cells activated by viral, bacterial, and parasitic infections. Production is normally short lived, usually for hours to a few days, and is seldom accompanied by detectable circulating concentrations. Several cytokines may cause the same response, and often cytokines are modulated (synergistic, antagonistic, or additive effects) by other cytokines. Actions often reflect cascade effects. Cytokine interaction results from binding to specific high affinity cell surface receptors and intracellular signal transduction cascades. The cytokine effect ultimately results in the production of DNA-binding proteins that influence gene transcription.

Recombinant DNA technology has led to the commercial availability of some (generally human) cytokines. By convention, recombinant products are designated by an “r” preceding the name of the cytokine and a designation of the species of origin (eg, rhIL indicating human origin, and rfeIFN indicating feline origin). Because cytokines tend to be conserved, human recombinant products often stimulate similar effects in animals. However, because systemic concentrations of a given cytokine impact many cytokine cascades, adverse effects and toxicity are not uncommon. The magnitude of the dose may be critical, eg, low doses of IFN appear to immunostimulate, whereas higher doses appear to be immu-nosuppressive. Except for rfeIFN-α (in cats) and rhIL-1 (in dogs), the pharmacokinetics of cytokines in dogs and cats have not been determined. Current doses generally are empirically derived.

Interferons are secreted by viral-infected cells. They bind to receptors on other cells and induce antiviral proteins that protect the cell from infection. However, IFN also have antiviral, antitumor, antiparasitic, and immuno-modulatory effects.

Two classes of IFN exist. Class I includes α, ω, and β interferons, whereas Class II includes γ interferons. IFN-γ, IFN-α, and IFN-ω appear to be produced by all nucleated cells. Cloned feline IFN-α cDNA appears to have similar pharmacokinetic properties to human IFN. IFN-β was originally described as being produced by fibroblasts but is secreted by many other cells. IFN-γ is produced by activated T and natural killer (NK) cells. Canine IFN-γ has been characterized, and a recombinant form has been produced; feline IFN-γ cDNA has also been cloned. IFN is produced on a large scale either through recombinant methods or by culturing stimulated cells, leading to the production of “natural” or “native” IFN products (denoted by “N”). Natural IFN are less concentrated and may contain a mixture of IFN types, as well as other cytokines.

Interferons interfere with viral RNA and protein synthesis, resulting in resistance to viral infections that occurs within a few minutes and peaks within a few hours. Their role in veterinary medicine is currently being defined. IFN-γ inhibits viral replication by stimulating the release of other IFN. Anecdotal data suggest that rhIFN-α confers clinical benefit to cats symptomatic for FeLV infection; however, there are no controlled studies with naturally occurring infections. The dosage of IFN is 30 IU rhIFN-α/cat, PO, sid for 7 days, on a 1-wk on, 1-wk off schedule. The optimal dose of other recombinant and natural hIFN is unknown but likely different. IFN also are induced by bacteria, fungi, and some protozoa; they facilitate activation of and intracellular and extracellular phagocytic killing of these organisms. IFN induce expression of class I and class II major histocompatibility molecules on antigen-presenting cells and thus enhance antigen presentation. IFN, and particularly IFN-γ, also influence T, B, and NK cell function. Oncogene expression is modulated in neoplastic cells. IFN inhibit cell proliferation of both normal and malignant cells and have numerous immunomodulating effects. Several human cancers respond to IFN therapy. At present, there are only preclinical data suggesting that IFN may be useful in the treatment of animal cancer.

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP

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