Treatment of Th1Mediated Autoimmune Diseases

We conducted the first anti-IFN-y therapy in Th-1-mediated diseases together with several clinics using a polyclonal anti-IFN-y antibody (both IgG and F(ab')2 antibody fragments) and in some cases, for comparison, a polyclonal anti-TNF-a. The antibodies were given intramuscularly once or twice daily for 5-6 days. Our studies include placebo-controlled, double-blind studies in patients with rheumatoid arthritis unresponsive to standard treatments (Sigidin et al. 2001) and in patients with secondary progressive multiple sclerosis (Skurkovich et al. 2001). In addition, we conducted smaller proof-of-principle studies in patients experiencing corneal transplant rejection (Skurkovich et al. 2002a), in psoriatic arthritis (Skurkovich et al. 1998), type I diabetes (Skurkovich et al. 2003a), uveitis (Skurkovich et al. 2003b), juvenile rheumatoid arthritis, auky-losing spondylitis and in several autoimmune skin diseases (Skurkovich et al. 2002b).

1.2.1 Rheumatoid Arthritis

An open-label study (23 patients) (Skurkovich et al. 1998) and subsequent double-blind, placebo-controlled studies (55 patients) of the use of anti-IFN-y compared to placebo and/or anti-TNF-a in patients with RA demonstrated statistically significant improvement in the key symptoms of the disease, using American College of Rheumatology (ACR) criteria (Skurkovich et al. 1998; Sigidin et al. 2001; Lukina et al. 2003; Lukina 2004). In the controlled study, anti-IFN-y was compared to a placebo as well as to anti-TNF-a in patients followed for 28 days. Results demonstrated that improvement with the use of anti-IFN-y was as good as and sometimes superior to anti-TNF-a with fewer side effects and higher remission rates (Lukina 2004). Ultrasound data indicated significant reduction of swelling in the synovial joint membrane in the anti-IFN-y group only (Lukina et al. 2003).

Commercially available TNF-a antagonists have brought many serious complications, such as systemic lupus erythematosus, reactivation of latent TB, liver problems, alopecia, lymphoma, and others (Michel et al. 2003; Cunnane et al. 2003; CDC 2004; Ettefagh et al. 2004; Hamilton 2004).

Giving IFN-y to patients with rheumatoid arthritis has been tried several times with varied results, including a positive effect, no effect, and exacerbation of the arthritis in comparison to a placebo (Cannon et al. 1993; Veys et al. 1997; Seitz et al. 1988). Given our positive results with an anti-IFN-y antibody, we speculate that positive results may be due to a suppressive effect on IFN-y production by the administration of IFN-y.

1.2.2 Multiple Sclerosis

Anti-IFN-y and anti-TNF-a antibodies were also used in an open-label study (22 patients), followed by a double-blind, placebo-controlled (45 patients) trial in patients with secondary progressive multiple sclerosis in which patients were followed for 1 year (Skurkovich et al. 2001). In the controlled trial, the group receiving anti-IFN-y showed a significant increase in the number of patients free of sustained EDSS (Expanded Disability Status Scale) progression and in mean time without sustained

EDSS progression as well as a significant increase in the number of patients without gadolinium-enhancing lesions using magnetic resonance imaging (MRI). No significant improvement was found using anti-TNF-a, which confirms other studies in multiple sclerosis patients in which anti-TNF-a was found ineffective (Lenercept Multiple Sclerosis Study Group 1999).

1.2.3 Corneal Transplant Rejection

Evidence supports the idea that reducing IFN-y could have a beneficial effect on corneal graft survival. For example, mice with immune responses manipulated to respond preferentially toward a Th-2 pathway experienced a sharp drop in the production of the Th-1 cytokine IFN-y, and a greater than 50% reduction in corneal graft rejection (Yamada et al. 1999).

In our study of patients suffering corneal transplant rejection after penetrating keratoplasty, 2-3 days after the start of a 6-day treatment course in which eye drops were administered 3-4 days a time, transplant transparency improved, and edema decreased in 10 of 13 patients (Skurkovich et al. 2002a). At the end of week 1, the transplant became almost fully transparent, eye inflammation disappeared, and visual acuity improved. In the remaining three patients, additional treatment courses were needed for comparable improvement. The improvement was maintained through follow-up averaging of 7 months. Four patients with corneal transplant rejection given anti-TNF-a also had comparable positive results (Kasparov et al. 2004). We plan to test our approach in transplant rejection of various organs using a monoclonal anti-IFN-y or anti-TNF-a, soluble receptors to IFN-y or TNF-a or anti-CD20.

1.2.4 Type I Diabetes

In a small group of three type I diabetic patients, a single 6-day course of anti-IFN-y antibodies was associated with a rise in C-peptide levels, a drop in blood glucose, and a reduction in the insulin dose (Skurkovich et al. 2003a). Larger clinical studies are planned using a humanized monoclonal antibody to IFN-y, to TNF-a, and possibly both anti-IFN-y and anti-TNF-a together.

1.2.5 Uveitis

In six patients with juvenile rheumatoid arthritis-associated uveitis, anti-IFN-y was found to be effective as an adjunct therapy in a comparison of standard therapy plus anti-IFN-Y vs standard therapy alone (Skurkovich et al. 2003b). In four of six patients, anti-IFN-Y when used with standard therapy appeared to halve the duration of the acute period, decrease the severity of symptoms during the acute period, and substantially increase the length of remission in these patients compared to standard therapy alone.

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