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

Abstract

Insights into the pathogenesis of inflammatory bowel diseases (IBDs) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are increased in inflamed intestinal tissues of patients with IBD. Loss-of-function variants of the IL23-receptor gene (IL23R) protect against IBD, and, in animals, blocking IL23 reduces the severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for the 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 also are emerging for the 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.

Keywords: Crohn’s Disease; Intestine; Therapy; Ulcerative Colitis.

Figure 1. Considerations of Cytokine Sources and Targets

Important considerations in designing therapies targeting cytokines include both the sources of and the responders to the targeted cytokine. Intestinal tissues contain a repertoire of immune cells and non-immune cells. Although the intent of targeting a given cytokine is generally to impact on its regulation of select immune cells (e.g. T cells) contributing to inappropriate immune responses, unintended consequences may occur due to cytokine-dependent essential roles in other immune and non-immune cells (e.g. epithelial cells, stromal cells, endothelial cells) within intestinal tissues and systemically. These unintended consequences may limit the efficacy of the therapy or result in unexpected adverse events.

Figure 2. IL23 and Th17 Cell Pathways

(A) Cytokines can be made up of multiple subunits. Some subunits are specific to 1 cytokine while others are shared by 2 or more cytokines. When a cytokine interacts with its receptor, which is also frequently composed of subunits (some shared), signals are initiated which induce gene expression patterns. Many cytokine receptors activate the JAK-STAT signaling pathway. In designing therapeutic agents, is important to consider whether to target the shared vs unique components of cytokines, cytokine receptors, signaling molecules, transcription factors or downstream regulated genes, because each can produce different outcomes. It also is important is to design therapeutic agents that reduce inflammatory effects while retaining immune regulatory effects. (B) IL23 signaling is mediated by the engagement of the heterodimeric IL23 cytokine (comprising IL23p19 and IL12p40) with its heterodimeric receptor (comprising IL23R and IL12Rβ1). This engagement activates the JAK-STAT signaling pathway, which in turn, regulates transcription of genes including IL17, IL21, and IL22. IL23 is important for maintenance of Th17 cells and for the generation of the more ‘pathogenic’ Th17 cells that contribute to intestinal inflammation. IL23 and its receptor share subunits with IL12 (IL12p40) and the IL12 receptor (IL12RB1), respectively. IL12 contributes to the differentiation of Th1 cells. Therefore, agents that target the IL12p40 subunit affect IL12 and IL23 signaling, and therefore, Th1 and Th17 cells. In contrast, agents that target IL23p19 disrupt only IL23 signaling and therefore the IL23-dependent regulation of Th17 cells, as well as other cells regulated by IL23. The figure shows agents targeting molecules at distinct levels in the pathway.

Figure 3. Cytokines That Signal via JAK Proteins

The JAK family of proteins are receptor tyrosine kinases comprising 4 members: JAK1, JAK2, JAK3, and TYK2. The different JAK family members, in cooperation with STAT family members, interact with and initiate signaling from a number of cytokine receptors. The figure shows select cytokines that signal through individual JAK members^,. It is important to note that JAK2 also mediates signaling from various growth factors and hormones.