Two papers published recently in Nature Medicine show that specific targeting of phosphatidylinositol 3-kinase-γ (PI3K-γ) with a drug can reduce the progression of disease in mouse models of rheumatoid arthritis and systemic lupus erythematosus (SLE).
For the treatment of chronic inflammatory diseases, specific targeting of PI3K-γ is thought to be crucial because, unlike class IA PI3Ks, which are ubiquitously expressed and are involved in numerous signalling pathways, PI3K-γ (a class IB PI3K) is expressed only by haematopoietic cells. Moreover, mice that lack PI3K-γ show impaired leukocyte migration and activation. Camps et al. identified two small-molecule inhibitors (AS-604850 and AS-605240) that are selective for PI3K-γ. In vitro, both compounds inhibited signalling triggered through PI3K-γ, as well as PI3K-γ-mediated chemotaxis of neutrophils and monocytes in response to several chemokines. Importantly, intracellular signalling and chemotaxis mediated by class IA PI3Ks were not affected by these inhibitors.
Because AS-605240 had the most potent inhibitory activity in vitro, the authors next tested whether AS-605240 could improve disease in two mouse models of rheumatoid arthritis. Indeed, paw swelling and joint inflammation induced by passive transfer of type-II-collagen-specific antibody were reduced by oral treatment with AS-605240 after the onset of arthritis. Similarly, oral administration of AS-605240 suppressed disease symptoms induced by immunization with type II collagen. In both models, the protective effect correlated with decreased neutrophil accumulation in the joints.
In the other paper, Barber et al. used the same inhibitor (AS-605240) and showed that it reduced the incidence and severity of glomerulonephritis and that it prolonged the lifespan of MRL-lpr mice, which are prone to an SLE-like disease.
Such developments provide hope for a new drug for the treatment of human autoimmune diseases.
References
ORIGINAL RESEARCH PAPER
Camps, M. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature Med. 11, 936–943 (2005)
Barber, D. F. et al. PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nature Med. 11, 933–935 (2005)
FURTHER READING
Ohashi, P. S. & Woodgett, J. R. Modulating autoimmunity: pick your PI3 kinase. Nature Med. 11, 924–925 (2005)
Rights and permissions
About this article
Cite this article
Bird, L. New drug for autoimmune diseases. Nat Rev Immunol 5, 748 (2005). https://doi.org/10.1038/nri1726
Issue Date:
DOI: https://doi.org/10.1038/nri1726