Pathophysiologic Rationale for Biological Therapies in IBD
Pathophysiologic Rationale for Biological Therapies in IBD
Purpose of Review: Inflammatory bowel disease is driven by an excessive immune response in the gut wall. This review summarises important new developments in understanding this immune response and the downstream mechanisms of intestinal injury, alongside their potential role in opening up new avenues of treatment.
Recent Findings: The evidence continues to accumulate that Crohn's disease is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarisation, but IL-21 may also be important. The p40 chain of IL-12 also associates with a novel p19 chain to form IL-23 which is also a potent Th1-inducing cytokine but the expression of IL-23 in Crohn's disease has not been reported. Progress in understanding the immunology of ulcerative colitis remains slow, but IL-13 produced by natural killer T cells may be involved. T-cell resistance to apoptosis occurs in Crohn's disease, and human and mouse studies indicate that the signalling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Fibroblasts and metalloproteinases continue be implicated in ulceration, fibrosis, and fistula formation.
Summary: Understanding the immunology of inflammatory bowel disease continues to underpin the vast majority of new therapies and identifies new targets. Novel approaches, such as exploiting the antiinflammatory role of cannabinoid receptors, may also prove productive in the future.
Over the past 10 years, huge advances have been made in our understanding of gut inflammation. The unravelling of immunopathogenic mechanisms has been critical to the discovery of new therapeutic targets, which has, in turn, driven the development of new biologic therapies. Progress has been greatest in Crohn's disease (CD), with the licensing and widespread usage of the anti-TNFa antibody infliximab. The breadth and complexity of immunemediated damage and repair in the gut is also beginning to be appreciated. The critical role of the epithelium in restoring mucosal integrity is now known, as is the role of mucosal fibroblasts in producing the matrix-degrading enzymes which cause ulcers and fistulae.
CD results from an excessive and persistent CD4 T helper cell type 1 (Th1) in the gut mucosa. Tissue from the gut of patients with CD contains abundant transcripts for IFNγ, and isolated mucosal T-cells secrete large amounts of INFγ (Fig. 1). Production of IL-12, one of the key cytokines involved in Th1 polarisation and differentiation, is markedly increased in subjects with CD. The increased expression of Th1 cytokines in CD is associated with T-bet, an IFNγ inducible novel member of the T-box family of transcription factors. IL-18 also drives Th1 cell differentiation, activates the transcription factors AP-1 and nuclear factor-κB (NF-κB) in T cells, and acts synergistically with IL-12. It is markedly upregulated in CD. Some IL-18 polymorphisms are also associated with increased susceptibility to inflammatory bowel disease (IBD). The IL-12 p40 chain can form a heterodimer with p19 protein to form a recently described cytokine, IL-23. In an IL-12p40 transgenic mouse model, constitutive p40 promoter activity is seen in the terminal ileum with high expression of IL-23 p19/p40 proteins in dendritic cells. There are no publications on IL-23 in CD.
(Enlarge Image)
T cells in Crohn's diseaseT cells in Crohn's disease receive signals which make them resistant to apoptosis, so they continue to secrete proinflammatory cytokines.
IL-21 is another newly described T-cell cytokine with homology to IL-3, IL-4, and IL-15, which enhances Th1 signalling and IFNγ production. It is increased in CD in comparison with UC and controls. IL-17 is a cytokine with strong proinflammatory activity. T-cell and macrophage production of IL-17 is significantly increased in both CD and UC, but not in infective or ischemic colitis.
Purpose of Review: Inflammatory bowel disease is driven by an excessive immune response in the gut wall. This review summarises important new developments in understanding this immune response and the downstream mechanisms of intestinal injury, alongside their potential role in opening up new avenues of treatment.
Recent Findings: The evidence continues to accumulate that Crohn's disease is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarisation, but IL-21 may also be important. The p40 chain of IL-12 also associates with a novel p19 chain to form IL-23 which is also a potent Th1-inducing cytokine but the expression of IL-23 in Crohn's disease has not been reported. Progress in understanding the immunology of ulcerative colitis remains slow, but IL-13 produced by natural killer T cells may be involved. T-cell resistance to apoptosis occurs in Crohn's disease, and human and mouse studies indicate that the signalling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Fibroblasts and metalloproteinases continue be implicated in ulceration, fibrosis, and fistula formation.
Summary: Understanding the immunology of inflammatory bowel disease continues to underpin the vast majority of new therapies and identifies new targets. Novel approaches, such as exploiting the antiinflammatory role of cannabinoid receptors, may also prove productive in the future.
Over the past 10 years, huge advances have been made in our understanding of gut inflammation. The unravelling of immunopathogenic mechanisms has been critical to the discovery of new therapeutic targets, which has, in turn, driven the development of new biologic therapies. Progress has been greatest in Crohn's disease (CD), with the licensing and widespread usage of the anti-TNFa antibody infliximab. The breadth and complexity of immunemediated damage and repair in the gut is also beginning to be appreciated. The critical role of the epithelium in restoring mucosal integrity is now known, as is the role of mucosal fibroblasts in producing the matrix-degrading enzymes which cause ulcers and fistulae.
CD results from an excessive and persistent CD4 T helper cell type 1 (Th1) in the gut mucosa. Tissue from the gut of patients with CD contains abundant transcripts for IFNγ, and isolated mucosal T-cells secrete large amounts of INFγ (Fig. 1). Production of IL-12, one of the key cytokines involved in Th1 polarisation and differentiation, is markedly increased in subjects with CD. The increased expression of Th1 cytokines in CD is associated with T-bet, an IFNγ inducible novel member of the T-box family of transcription factors. IL-18 also drives Th1 cell differentiation, activates the transcription factors AP-1 and nuclear factor-κB (NF-κB) in T cells, and acts synergistically with IL-12. It is markedly upregulated in CD. Some IL-18 polymorphisms are also associated with increased susceptibility to inflammatory bowel disease (IBD). The IL-12 p40 chain can form a heterodimer with p19 protein to form a recently described cytokine, IL-23. In an IL-12p40 transgenic mouse model, constitutive p40 promoter activity is seen in the terminal ileum with high expression of IL-23 p19/p40 proteins in dendritic cells. There are no publications on IL-23 in CD.
(Enlarge Image)
T cells in Crohn's diseaseT cells in Crohn's disease receive signals which make them resistant to apoptosis, so they continue to secrete proinflammatory cytokines.
IL-21 is another newly described T-cell cytokine with homology to IL-3, IL-4, and IL-15, which enhances Th1 signalling and IFNγ production. It is increased in CD in comparison with UC and controls. IL-17 is a cytokine with strong proinflammatory activity. T-cell and macrophage production of IL-17 is significantly increased in both CD and UC, but not in infective or ischemic colitis.