Wednesday, September 30, 2015

α-IL23, not α-IL17 antibody blockade, shows protection in IBD model

Previous studies indicated that cytokines IL-23 and IL-17 act in concert to induce and perpetuate autoimmune inflammation. This is certainly true for psoriatic skin inflammation.

However, two new back-to-back studies in journal Immunity provided evidence that when it comes to intestine inflammation, role of IL-23 and IL-17 goes in opposite direction. Here, blockade of IL-17 exacerbate while blockade of IL-23 inhibits intestine pathology and gut wall permeability.

Both studies came from research groups working in biotech/biopharma (Daniel Cua's group at Merck Research Laboratories and Jennifer Towne's group at Amgen [presently at Janssen]). Both studies reached similar conclusions. 

Here, the authors treated colitis-prone mice with blocking antibodies specific for IL-23 or IL-17 cytokine family. Surprisingly, both α-IL17A or α-IL17RA treatment worsened gut pathology, while α-IL23 (p40 or p19 subunits) antibody showed protection.

Unlike α-IL23, α-IL17RA antibody treatment was associated with increased gut wall permeability (serum sCD14 and LBP), implying IL-17 role in gut health.

Similar increased gut leakage (with FITC-dextran) was observed by Merck's team in chemical irritant DSS-induced GI inflammation model in IL-17KO mice (though Amgen's team did not observe it in DSS mouse model with α-IL17 treatment. It could be that α-IL17 antibody blockade did not fully inhibit IL-17 action as it could be expected in IL-17KO mice).

Additional experiments showed that γδ T cells were the main producers of gut IL-17 in DSS model and that γδ T cell KO mice showed the same increased GI tract permeability as IL-17KO mice.

Finally, Merck's team showed that (a) γδ T cell-derived IL-17 production in the gut were mostly IL-23 independent and (b) IL-23rKO mice were protected against worsening GI wall pathology.

In overall, these two studies suggest that local gut tissue associated IL-23 independent but γδ T cell-derived IL-17 production plays a protective role in gut permeability. Basically, this means that α-IL23 blockade, but not α-IL17 pathway inhibition, would most likely provide benefits to patients suffering from GI tract idiopathic inflammation.

David Usharauli

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