Autoimmune diseases are connected with disturbances in cytokine synthesis, and therapy with IFN-gamma blockers is their main pathogenetic treatment.

Development of autoimmune process in the organism is mainly due to disturbances in cytokine production. Hyperproduction of cytokines can be induced by certain viruses, bacteria, genetic factors, and other triggers. Cytokines act in an interrelated immune cascade with interferon-gamma (IFN-gamma) playing a central role. Blocking IFN-gamma is the safest and most effective method of treatment of TH1-mediated autoimmune diseases, although blocking other cytokines in the cascade may lead to some therapeutic effect as well. Disturbances in the synthesis of IFN-gamma and, possibly, IFN-alpha may lead to autoantigen formation. Antibodies to IFN-gamma have shown very pronounced therapeutic effect in multiple autoimmune conditions, especially in autoimmune skin diseases. Anticytokine therapy that we have pioneered may be the main pathogenetic method of treatment of a variety of autoimmune conditions.

Anticytokine therapy, especially anti-interferon-gamma, as a pathogenetic treatment in TH-1 autoimmune diseases.

We pioneered anticytokine therapy (ACT) in 1974 and 1989, proposing to remove interferon (IFN) and tumor necrosis factor (TNF)-alpha together with IFNs to treat various autoimmune diseases, including AIDS. This hypothesis was confirmed in different laboratories and opened a new line to produce and test different anticytokines. We have had good, sometimes striking results treating various Th1-mediated autoimmune diseases, including inflammatory skin diseases, using anti-IFN-gamma and sometimes anti-TNF-alpha. Anti-IFN-gamma may be a universal treatment for these conditions. Because TNF-alpha inhibitors, now successfully used in certain autoimmune disorders, have many severe side effects, there are opportunities for the development of other ACT and TNF-alpha antagonists with fewer side effects.

Anticytokine therapy, particularly anti-IFN-gamma, in Th1-mediated autoimmune diseases.

Anticytokine therapy was proposed in 1974 in Nature, in which it was stated that hyperproduced interferon can cause autoimmune disease and anti-interferon can be therapeutic. In 1989, the use of antibodies to tumor necrosis factor-alpha in combination with antibodies to certain types of interferon was proposed to treat various autoimmune diseases, including AIDS. The first anticytokine therapy was conducted in 1975. Anti-interferon-gamma has brought improved and often striking results in the treatment of various T-helper 1-mediated autoimmune diseases, including inflammatory skin diseases. Anti-interferon-gamma may be a universal treatment for these conditions. In AIDS and other virus-induced autoimmune diseases, the virus may stimulate cytokines (interferons), which increase, rather than halt, viral replication. Tumor necrosis factor-alpha inhibitors have also shown good clinical results, however, they may result in complications and are ineffective in some autoimmune diseases.

Anti-interferon-gamma antibodies in the treatment of autoimmune diseases.

Interferon (IFN)-gamma is an important immune regulator in normal immunity. When IFN gamma production is disturbed, various autoimmune diseases (ADs) can develop, in which we suggest that anti-IFN gamma could have a beneficial effect. Depending on the cell type in which IFN gamma synthesis is disturbed, different clinical manifestations may result. We have also proposed to remove tumor necrosis factor (TNF)-alpha, together with certain types of IFNs, to treat various ADs and AIDS, also an autoimmune condition. Anti-IFN gamma has been tested in several T-helper cell (Th1) ADs, including rheumatoid arthritis (RA), multiple sclerosis (MS), corneal transplant rejection, uveitis, Type I diabetes, schizophrenia (anti-IFN gamma and anti-TNF alpha), and various autoimmune skin diseases (alopecia areata, psoriasis vulgaris, vitiligo, pemphigus vulgaris and epidermolysis bullosa). A strong, sometimes striking, therapeutic response followed administration of anti-IFN gamma, indicating that it may be a promising therapy for Th1 ADs.

Treatment of corneal transplant rejection in humans with anti-interferon-gamma antibodies.

PURPOSE: To determine efficacy of anti-human interferon-gamma F(ab')2 (Fabs) in treating corneal transplant rejection after penetrating keratoplasty. DESIGN: Interventional case series. METHODS: Anti-interferon-gamma Fabs derived from goat antihuman interferon-gamma antibodies were used for instillations in 13 patients (13 eyes) who experienced corneal transplant rejection after penetrating keratoplasty. Fabs were administered in one or three treatment course(s) as eyedrops given three times daily for 7 to 10 days. RESULTS: In 10 patients, 2 to 3 days after start of one treatment course, transplant transparency improved, and edema decreased. At the end of week 1, the transplant became almost fully transparent, and eye inflammation disappeared. Visual acuity increased from 0.2 to 0.3. In the other three patients, three treatment courses were needed for comparable improvement. Improvement was maintained through follow-up-an average of 7 months. CONCLUSION: Antihuman interferon-gamma Fabs may be safe and effective in halting corneal transplant rejection after penetrating keratoplasty.