Introduction

Anticytokine therapy was pioneered by S. Skurkovich, who in 1974 published in Nature the proposal that the hyperproduction of interferon (IFN) (a cytokine) can bring autoimmune disease and that neutralization of IFN could be therapeutic (Skurkovich et al. 1974). This proposal was based on data describing the mechanism of IFN action (Skurkovich et al.1973). It was postulated that IFN production was a part of the immune response and that any disturbance of IFN production could lead to immune system dysregulation and vice versa (Skurkovich et al. 1973, 1982). In other words, a disturbance of IFN synthesis can bring disease. In 1975, IFN was found in the blood of autoimmune patients and the first anticytokine therapy was tested (Skurkovich and Eremkina 1975).

Many years ago, it was proposed that anticytokine therapy could be beneficial in treating a wide variety of autoimmune diseases and diseases of supposed autoimmune genesis, in which disturbed IFN synthesis is a common mechanism of pathology; these included prolongation of skin allografts, collagenoses, rheumatism, hemolytic anemia, immune form of idiopathic thrombocytopenic purpura, eczemas, nephritis, myasthenia gravis, Hashimoto disease, autoimmune diseases of the organs of sight and hearing, multiple sclerosis, Meniere's disease, Parkinson's disease, pemphigus, schizophrenia and possibly some mental derangements, psoriasis and Crohn's disease (Skurkovich et al. 1974, 1975, 1977, 1991). This was considered a radical proposal at the time, but since then the literature supporting use of anticytokine therapy as a universal treatment in various Th-1-mediated autoimmune diseases has accumulated.

Studies in experimental rodent models of autoimmune diseases confirm the hypothesis of the role of IFN-y in autoimmunity. In these models, IFN-y can trigger or exacerbate disease, as in thyroiditis, anterior uveitis, and autoimmune neuritis (Kawakami et al. 1990; Egwuagu et al. 1999; Hartung et al. 1990), and anti-IFN-y can bring beneficial results, such as in presenting type I diabetes (Debray-Sachs et al. 1991; Nicoletti et al. 1997), and treating experimental autoimmune thyroiditis (Tang et al. 1993),and neuritis (Tsai et al. 1991). The administration of IFN-a and -y to patients for the treatment of cancer and other diseases has led to the triggering or exacerbation of a great variety of underlying autoimmune diseases (Miossec 1997). It was also found that mice deficient in the IFN-y receptor are less susceptible to collagen-induced arthritis (Kageyama et al. 1998). Thus, in the laboratory, research supports our hypothesis that disturbed IFN-y production can lead to disease. The central role of IFN-y in the pathogenesis of many organ-specific autoimmune diseases will be discussed below.

In 1989, it was clear that IFN-y induces other cytokines, such as TNF-a. We first proposed to remove TNF-a together with pH labile IFN-a in autoimmune diseases and AIDS, which is also a disease with autoimmune components (Skurkovich et al. 1989). (IFN-y is pH labile, while IFN-a is normally pH stable.) Now TNF-a antagonists have been commercialized by several companies to treat several autoimmune diseases, including rheumatoid arthritis, Crohn's disease, and psoriasis.

Though we were the first to propose treating autoimmune patients with anti-TNF-a, we have particularly investigated use of anti-IFN-y; at the same time we have compared the effectiveness of anti-IFN-y and anti-TNF-a in various autoimmune diseases. Our investigations have shown that anti-IFN-y may have clinical effects that are as good as and sometimes superior to anti-TNF-a. Based on the differentiation of T

helper cells into Th-1, Th-2, Th3, and Th0 subsets (Mosmann and Sad 1996), autoimmune and allergic diseases are sometimes distinguished as Th-1 or Th-2 diseases, respectively, depending on whether they are mediated by a polarization of T helper cells toward the Th-1 or Th-2 subset. Organ-specific autoimmune diseases, considered here, are generally characterized by the production of Th-1, or proinflammatory cytokines, including IFN-y, IL-2, TNF-P, and others. TNF-a is also considered a proinflammatory cytokine.IFN-y and TNF-a in many cases work syn-ergistically and have many of the same effects.

Based on our hypothesis and accumulating data in the laboratory and clinic supporting the importance of IFN-y and TNF-a in the pathogenesis of Th-1-mediated conditions, we have clinically tested the use of anticytokine therapy, in this case anti-IFN-y and sometimes anti-TNF-a antibodies, in the treatment of a broad range of these diseases. We present here our data with particular attention to skin diseases. We also will review the laboratory evidence supporting this approach.

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