Interleukin-2 inhibitors in autoimmune disease

Abstract

T-lymphocytes orchestrate both the initiation and propagation of immune responses largely through the secretion of interleukin-2 (IL-2). IL-2 is primarily involved in the regulation of T-lymphocytes proliferation but also activates natural killer (NK), B- and lymphokine-activated killer (LAK) cells. Inappropriate responses of T-lymphocytes are associated with a range of immune diseases, including allergies and autoimmune diseases. Because of the key role of IL-2 in promoting the growth of T-cells involved in autoimmune disease, there is significant interest in inhibition of IL-2 as a therapeutic modality. Compounds such as cyclosporin A (CsA), rapamycin and FK506 from microbial sources are mainly used to combat transplant rejection. Several compounds, including leflunomide and mycophenolate mofetil were developed to selectively inhibit nucleotide synthesis in T-cells and hence block IL-2 synthesis. Several patents have claimed the use of peptides and antibodies to inhibit IL-2 and T-cell activation. Alternative approaches to inhibit IL-2 formation include the intracellular regulation of calcium and potassium levels using small molecules. Several companies are actively pursuing the use of small molecules to inhibit transcription factors such as activator protein-1 (AP-1), nuclear factor-κB (NF-κB) and nuclear factor of activated T-cells (NF-AT) that are involved in the production of IL-2. Recent patent activity suggests this is an active area of drug discovery in the pharmaceutical industry.

• activator protein 1
• anti-inflammatory compounds
• autoimmune disease
• cyclosporin A
• FK506
• interleukin-2
• leflunomide
• mycophenolate mofetil
• nuclear factor κB
• nuclear factor of activated cells
• rapamycin
• T-lymphocytes
• transcription factors