Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

Abstract

Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

Validation of Neutrophil CD64 Blood Biomarkers to Detect Mucosal Inflammation in Pediatric Crohn’s Disease

“…Alternatively, elevations in neutrophil CD64 expression may be limited to a CD phenotype driven largely by IFNγ. 30, 31 Lastly, although CD64 upregulation in response to an inflammatory trigger (like IFNγ) predominates, there is the possibility of increased neutrophil CD64 receptor avidity rather than absolute CD64 upregulation. CD64 and the other activating Fcγ receptors have been found to increase inside-out signaling (avidity) where ligand binding capacity to Fcγ receptors increases with no change in CD64 cell surface expression.…”

Potential markers for early diagnostics of Colorectal cancer and Inflammatory bowel disease in humans : intestinal microorganisms and immune system (teammates or rivals)

“…The suggested mechanism was the up regulation of anti-apoptotic factors. In blood sera and tumor biopsies of CRC patients, increased IL-6 concentrations were detected [25,26].…”

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

“…58 IL-12 activates STAT4, a necessary transcription factor in the long-term induction of a Th1 response. 59 Overexpression of IL-12 is observed in Crohn’s disease and other human inflammatory conditions, 60,61 but genetic ablation of the IL-12p35 subunit exhibited no protective effect in a mouse model of brain inflammation 62 and even a deleterious response in a mouse model of arthritis.…”

“…IL-23 blockade as opposed to blockade of downstream mediators, such as IL-17, has specific therapeutic advantages in IBD, including the ability to modulate the gene expression and pathogenicity of Th cell subsets including Th17 cells. 58,67–71 IL-23 also has broad effects on other pro-inflammatory cytokines and cell types. In the T cell transfer model of colitis, transfer of IL-23R− /− T cells leads to reduced T cell infiltration into the colon and changes the equilibrium of Th17 and FoxP3+ T regulatory cells, which is associated with attenuation of intestinal inflammation, down-regulation of IL-21 and IL-22 levels, and upregulation of the anti-inflammatory cytokine IL-10.…”