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Interfering with interferons in inflammatory bowel disease

Early experience of fontolizumab, a humanised anti-interferon γ antibody, in active Crohn’s disease has shown that the drug caused a significant decrease in endoscopic severity scores and CRP and was reasonably well tolerated. Fontolizumab may be worthy of further clinical trials

Interferons (IFN) are cytokines produced by immune cells in response to virus, bacteria, parasites, and tumour cells. Interferons exhibit immunomodulatory and antitumour activity in addition to the antiviral activity which defined the interferons. Three types of interferons are recognised in humans. Type I interferons consist of 14 alpha isoforms and beta, epsilon, omega, and kappa isoforms. Type I interferon receptor is composed of two chains, IFNAR-1 and IFNAR-2, and the signal transduction pathway involves constitutively expressed Janus family kinases Jak 1 and Tyk 2 with activation of Stat1, Stat2, Stat3, and Stat5. Interferon γ (IFN-γ) is classified as a type II interferon. Type II interferon receptor is composed of IFNGR-1 and IFNGR-2 subunits and the signal transduction pathway involves Jak 1 and Jak 2 kinases with phosphorylation and activation of Stat1 (fig 1). The third type consists of interferon lambda with three isoforms.



 Figure 1 
 Binding of interferon γ to type II interferon receptor composed of IFNGR-1 and IFNGR-2 subunits. This leads to activation of Janus family kinases Jak1 and Jak2 and phosphorylation of Stat1. Stat1 homodimers are translocated into the nucleus with initiation of gene transcription.



IFN-γ drives expression of MHC class II on antigen presenting cells, increases chemokine secretion, and activates macrophages, lymphocytes, and endothelial cells. In addition to activation of Stat1, IFN-γ also activates Raf-1 and β-Raf kinases with resulting activation of p42 mitogen activated protein kinase. A further signalling pathway activated by interferons is the ubiquitously expressed phosphatidylinositol 3′ kinase enzymes. In inflammatory bowel disease, both Crohn’s disease (CD) and ulcerative colitis (UC), plasma and tissue concentrations …