Current and emerging biological inflammatory bowel disease (IBD) treatments targeting the mucosal immune cells and pathways described in this review
| Biological target | Drugs | Description | |
|---|---|---|---|
| Innate immune cell signalling | |||
| TNFα | Infliximab, adalimumab, certolizumab pegol | The most well established biological treatment for IBD likely acts by neutralisation of inflammatory macrophage derived TNF. However there is also evidence that these agents also promote T cell apoptosis and may induce regulatory macrophages. | |
| TLR | TLR9 | DIMS0150 (Kappaproct), BL-7040 | TLR activation in response to bacterial recognition such as TLR9 binding to unmethylated CpG motifs activate downstream inflammatory cascades that may contribute to disease and perpetuate inflammation in response to commensals. TLR signalling is also required for maintenance of a healthy epithelium, and MyD88 deficient mice have increased susceptibility to experimental colitis. |
| MyD88 | RDP58 | ||
| T cell activity | |||
| T cell proliferation | CD3 | Visilizumab | An exaggerated T cell response is a fundamental hallmark of IBD, and these treatments are therefore aimed at limiting T cell proliferation and expansion, but will also inhibit protective and regulatory T cell functions. |
| CD25 | Basiliximab, daclizumab | ||
| Protein kinase C inhibitor | Sotrastaurin | ||
| Chemotaxis | CCR9 | CCX-025, CCX282-B | Inhibits the CCR9 chemokine receptor and intestinal homing of T cells in response to CCL25 chemokine ligand. |
| α4β7 integrin | Vedolizumab, natalizumab, ELND-004, AJM-300, etrolizumab | Blocks the α4β7 integrin, which interacts with MAdCAM-1 on intestinal endothelial cells and mediates gut T cell homing. | |
| MAdCAM-1 | PF-547659 | ||
| IP-10 | MDX-1100 | Blocks interferon inducible protein-10 (IP-10), also known as CXCL10 (high levels seen in UC), which binds to CXCR3 and recruits activated T cells, NK cells and eosinophils. | |
| Regulatory T cells | OvaSave | Injection of autologous, OVA-expanded regulatory T cells. | |
| Pro-inflammatory cytokines— These have traditionally been considered in the context of T cells; many of the following cytokines are also produced and/or act on other immune cells such as innate lymphoid cells (ILCs) | |||
| JAK | Tafocitinib | Inhibits JAK-STAT signalling pathway and thereby blocks subsequent inflammatory cytokine production; including IL-2, 4, 7, 9, 15, and 21. | |
| IL-12/23 | Ustekinumab, SCH900222, briakinumab | Produced by myeloid cells, IL-12 and IL-23 share their p40 subunit and promote pro-inflammatory Th1 and Th17 differentiation; but more recently have been also been shown to act on ILCs. | |
| IL-17 | Secukinumab, brodalumab, vidofludimus | Produced by Th17 and ILCs, IL-17 is considered pro-inflammatory but also has important homeostatic function. Notably secukinumab (anti-IL-17A) appears to worsen CD. | |
| IFNγ | Fontolizumab | IFNγ is a classical Th1 cytokine; also produced by inflammatory ILCs. | |
| IL-13 | QAX576, anrukinzumab, tralokinumab | IL-13 is a cytokine associated with UC, whose production by NKT cells appears essential in murine oxazolone colitis. | |
| IL-6 and IL-6R | Tocilizumab, PF04236921, C326 | IL-6 produced by myeloid cells upregulates anti-apoptotic genes in T cells and promotes inflammatory for example, Th17 cell expansion. | |
CD, Crohn's disease; NKT, natural killer T cells; TLR, toll-like receptor; TNF, tumour necrosis factor; UC, ulcerative colitis.