Localization of Major Peptide Autoepitopes for Nucleosome Specific T Cells of Systemic Lupus Erythematosus (20032/99016)
Investigators at Northwestern University have identified peptides localized to distinct regions of histone proteins that are recognized by autoimmune T-cells in Systemic Lupus Erythematosus (SLE). These peptides, when administered in a mouse model of SLE, delay onset as well as significantly decrease the severity of the disease. The use of these peptides in the treatment of SLE would offer a more specific intervention by targeting the immune cells that mediate the pathogenic effects, but without the generalized immunosuppressive and toxic effects of the drugs currently being used. Importantly, these peptides appear to be effective even when the autoimmune disease is already established. The peptides can also be used as a sensitive diagnostic and/or prognostic tool for tracking autoimmune T-cells that may appear long before symptoms of the disease itself are manifested.BACKGROUND and SIGNIFICANCE: SLE is a debilitating autoimmune disease affecting about 50 people per 100,000 overall in the U.S.; the incidence rises to 1 in 700 in young women of childbearing age. The Lupus Foundation of America estimates that approximately 1.5 million Americans have a form of this chronic, lifelong disease. The abnormal immune response in SLE is systemic and involves a complex web of polyclonal T and B cell hyperactivity and multiple susceptibility genes. Lupus patients produce pathogenic autoantibodies that bind to normal physiological constituents that results in inflammation and tissue damage, particularly within the kidneys, joints, skin and brain. These autoantibodies recognize complexes of DNA and histone proteins called nucleosomes.
These inventors addressed how autoimmune "lupus" T helper cells recognize nucleosome-derived peptides by cloning these pathogenic T cells and defining the specificities of their receptors. They determined that lupus T cells recognize peptides localized to distinct regions of histones H1, H2B, H3 and H4 (Lu L et al, J Clin Invest 104: 345, 1999). Interestingly, the autoimmune T cells of lupus recognized these critical peptides in a highly cross-reactive fashion. Several of these peptides, when administered to young lupus prone mice in a soluble high-dose form, were found to delay the onset of severe lupus nephritis. Long-term therapy in adult mice with established nephritis prolonged their survival and stopped the progression of the disease. One of the peptides, which had a tolerogenic effect on both autoimmune T and B cells, reversed the kidney disease and allowed mice to live a nearly normal lifespan (Kaliyaperumal A et al, J Immunol 162: 5775, 1999, Kaliyaperumal A et al, J Immunol, 168:2530, 2002). More recently subcutaneous administration of the peptide at low doses (1 µg) delayed onset of severe lupus nephritis and generated regulatory T cells that suppressed autoantibody production in lupus prone mice, markedly prolonging their survival (Kang H-K et al, Arthritis and Rheumatism, 46 (Suppl): S225, #526, 2002).
In summary these inventors have identified a treatment for SLE using nucleosomal-derived peptides that:
Are naturally occurring and do not generate anaphylactic/allergic reactions. Are effective at low doses and by subcutaneous administration in an animal model of lupus. Generate long-lasting regulatory T cells (via subcutaneous administration) that suppress pathogenic autoantibody production and lupus nephritis. Are recognized by autoimmune T and B cells of all lupus patients tested irrespective of their HLA haplotype.
U. S. Patent No. 6,468,537 issued October 22, 2002 as follows and Northwestern is interested in licensing this technology.
Type of Offer: Licensing
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