Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis

Nat Med. 2005 Sep;11(9):936-43

Speaker: 鄭自勝                 Time: 2005/09/21 14:10-15:00

Commentator: 王志堯 醫師       Place: Room 601

Abstract:

Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease that affects 0.5-1% of the population, commonly leads to significant disability and reduction in quality of life. Chemokines and other chemoattractants have been detected in inflamed joints, and responsible for recruitment of leukocyte into the joints, leads to the destructive process, one of the hallmarks in the pathogenesis of RA¹. Blocking individual chemoattractants or their receptors are rational therapeutic strategies by preventing leukocyte chemotaxis and activation. PI3K have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders. But the lack of isoform selective PI3K inhibitors brings about significant side effects in therapy. The PI3Kγ isoform is mainly restricted to hematopoietic system and has a pivotal role in mediating leukocyte chemotaxis, activation, and mast cell degranulation, as shown by gene-targeting studies². Despite there are several drugs used to cure RA, no effective therapies with limited side effects are available³. So that pharmacological blockade of PI3Kγ might offer an innovative therapeutic strategy for RA and other inflammatory diseases.

References:

1.Szekanecz, Z., Kim, J. & Koch, A.E. Chemokines and chemokine receptors in rheumatoid arthritis. Semin. Immunol. 15, 15–21 (2003).

2.Sasaki, T. et al. Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040–1046 (2000).

3.Smolen, J.S. & Steiner, G. Therapeutic strategies for rheumatoid arthritis. Nat. Rev. Drug Discov. 2, 473–488 (2003).