IL-12, IL-23 and IL-17 Immunology Reagents for IBD

To state that the treatment of Crohn's disease and ulcerative colitis was transformed by the arrival of monoclonal antibodies targeting TNF is no exaggeration. Nevertheless, despite considerable advances in our understanding of the optimal use of these drugs in treating IBD, a clear unmet need remains in the form of patients either unresponsive to anti-TNF therapy or those who show initial response but subsequently lose response over time. Two decades after the licensing of the first anti-TNF monoclonal antibody for Crohn's disease, 2016 finally saw the FDA and the European Medicines Agency (EMA) approve therapeutic targeting of a new cytokine with ustekinumab. More specifically, ustekinumab targets a cytokine subunit common to both IL-12 and IL-23.

Differential regulation of IL-12–IL-23 release.

Macrophages and dendritic cells, as tissue sentinels, have a key role in maintaining immune homeostasis in the intestine. This function particularly applies in the context of IBD as demonstrated by the identification of a number of putative key driver genes in IBD that are enriched for macrophage-specific gene signatures. Many agonists of pattern recognition receptors augment the production of both IL-12 and IL-23, by activating the transcriptional regulator C-Rel of the nuclear factor-KB (NF-KB) family and also through epigenetic mechanisms.

Various studies have begun to decipher differential regulators of IL-12 and IL-23 production, and it has become apparent thatspecific microbial ligands signalling through receptors such as Toll-like receptor 2 (TLR2), nucleotide-binding oligomerization domain-containing protein 2 (NOD2), dectin 1 and dectin 2 can favour IL-23 production, as do certain damage-associated molecular patterns such as ATP or prostaglandin E2. The presence of certain cytokines, such as IL-4 or IL-13, enhance the production of IL-12p35, and T_H1-cell-derived IFNγ enhances IL-12 production in a positive feedback loop. In vivo, the complex microenvironment of the commensal microbiota drives dendritic cells of the ileal lamina propria towards IL-23 production, and microbes adhering to intestinal epithelial cells such as segmented filamentous bacteria, Citrobacter rodentium or Escherichia coli O157 also preferentially trigger T_H17 responses in an IL-23-dependent manner.

Important Targets of IL-12 and IL-23

An important target of both IL-12 and IL-23 are ILCs themselves. Developmentally rooted in the lymphoid lineage, ILCs are an essential, self-maintained component of the innate immune system. ILCs execute important effector functions rendering them key regulators of tissue homeostasis, repair, remodelling, microbial defence and antitumour immunity, particularly in intestinal inflammation. As ILCs possess few sensory elements for the recognition of extrinsic non-self signals, they depend on myeloid cells to translate environmental cues into a cytokine profile that modulates ILC function to further instruct lymphocyte responses.

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Antigens

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