Chapter 40: Interferons

Interferons

Toshiroh Iwasaki, Tokyo, Japan

Interferons (IFNs) belong to the class of cellular proteins referred to as cytokines. These proteins are secreted by cells of the immune system in response to viral infection or neoplasia. IFNs exert inhibitory effects on viral and cell proliferation and affect the immune regulatory system and inflammatory reactions.

Classification

IFNs are classified as either type I or type II. Type I IFNs bind to the cell via the INFAR receptor. Type I IFNs are further classified as either α, β, or ω. IFN-γ is the only cytokine classified as a type II IFN. Mature IFN-γ forms a homodimer that binds to the IFN-γ receptor complex by which it exerts its effect.

Recombinant feline IFN-ω (rFeIFN-ω) and recombinant canine IFN-γ (rCaIFN-γ) are available in only a few countries, but various types of recombinant human IFNs are more widely available. In Japan natural human IFN-α has been approved for the treatment of bovine diarrhea. No clinical trials have been conducted to study the efficacy of IFN-α in treating skin diseases in small animals.

Mode of Action

IFNs are antiviral and also demonstrate anti-oncogenic properties. IFNs are induced directly by the presence of viruses, and when large amounts of double-stranded ribonucleic acid (RNA) are found within the cell in association with Toll-like receptors, IFNs are synthesized and secreted to surrounding cells. IFNs also are induced by other cytokines such as interleukin-1 (IL-1), IL-2, IL-12, and tumor necrosis factor.

IFN-α and IFN-β are produced by various types of cells, including lymphocytes, macrophages, and fibroblasts. They also activate macrophages and natural killer lymphocytes and directly inhibit tumor cell proliferation. IFN-γ is produced by activated type 1 helper T cells (T_H1 cells) and has an immunomodulating effect on T_H1/T_H2 cytokine balance.

Previous studies have shown that inflammatory mediators such as granulocyte-monocyte colony-stimulating factor (GM-CSF) are produced by keratinocytes in atopic dermatitis lesions, and GM-CSF has been shown to be significantly increased in human with atopy. An in vitro study demonstrated that rCaIFN-γ suppressed messenger RNA transcription of GM-CSF in cultured canine keratinocytes (Shibata et al, 2010).

Clinical Application of Interferons in Small Animal Dermatology

Interferon-α and Interferon-β

There are a number of anecdotal reports of the treatment of animal skin diseases using recombinant human IFN-α2b (rHuIFNα2b) and IFN-α2a (rHuIFNα2a). In one published report, oral rHuIFNα2b was used for the management of idiopathic recurrent canine pyoderma at a dosage of 1000 U/ml/day and was found to provide transient benefits compared with placebo (Thompson et al, 2004). rHuIFNα was administered at a dosage of 1 million U/kg three times a week SC for 2 weeks to treat canine papillomavirus–associated hamartoma and squamous cell carcinoma, but the efficacy of the therapy in these conditions is uncertain (Callan et al, 2005).

Interferon-γ

rCaIFN-γ is produced by silkworms via the transfer of canine full-length IFN-γ genes. It was launched on the Japanese market for the treatment of canine atopic dermatitis in 2005. Six subcutaneous injections of rCaIFN-γ given in two consecutive weeks modified T_H1 and T_H2 cytokine messenger RNA profiles for IL-4 and IFN-γ toward T_H1 cytokine predominance. Treatment yielded improvement of clinical signs in 10 atopic dogs (Iwasaki et al, 2005). It also decreased total immunoglobulin E in sera, although levels of allergen-specific immunoglobulin E were not determined.

Recently a randomized clinical trial of rCaIFN-γ was performed in 63 atopic dogs in which rCaIFN-γ was administered at a dosage of 10,000 U/kg three times a week SC for 4 weeks, followed by once-a-week administration for 4 weeks. Seventy-two percent of the dogs treated with rCaIFN-γ showed improvement (defined as >50% reduction of pruritus), compared with only 20% in the control group given antihistamine spray (Iwasaki and Hasegawa, 2006). Based on this study the manufacturer recommended a dosage of rCaIFN-γ of 10,000 U/kg three times a week SC.

The dosage of rCaIFN-γ required for the treatment of canine atopic dermatitis was investigated further in 2010. Yasukawa and colleagues evaluated the efficacy of low-dose rCaIFN-γ in an open-label randomized clinical trial that tested two doses, 2000 U/kg and 5000 U/kg. The efficacy of the 5000-U/kg dose was found to be comparable to that of the 10,000-U/kg dose, whereas the 2000-U/kg dose was less effective than either of the larger doses (Yasukawa et al, 2010).

Although the mode of action of this drug has not yet been clarified, modification of the T_H1 and T_H2 cytokine profiles may play some role in the improvement of clinical signs in canine atopic dermatitis. Only a few adverse effects, including pain at the injection site, were noted.

Hyperplastic dermatosis of the West Highland white terrier, known as epidermal hyperplasia or armadillo Westie syndrome, is a severe and chronic hyperplastic disease associated with Malassezia overgrowth. Although the prognosis for this disease usually is guarded even with successful control of Malassezia, one West Highland white terrier with the disease showed marked improvement of clinical signs (pruritus and erythema) when treated with rCaIFN-γ at a dosage of 10,000 U/kg SC, initially three times weekly for 2 weeks and then as a maintenance treatment every 7 to 14 days.

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