Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease

Abstract

In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD. In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD. IBD is a chronic inflammatory disorder that is placing a growing burden on healthcare systems1Chang J.T. Pathophysiology of inflammatory bowel diseases.N. Engl. J. Med. 2020; 383: 2652-2664Crossref PubMed Scopus (326) Google Scholar, 2Kaplan G.G. Windsor J.W. The four epidemiological stages in the global evolution of inflammatory bowel disease.Nat. Rev. Gastroenterol. Hepatol. 2021; 18: 56-66Crossref PubMed Scopus (311) Google Scholar. The incidence of IBD in Western countries is 12–26 per 100,000 people per year and is rapidly increasing in newly industrialized countries in Asia and Latin America2Kaplan G.G. Windsor J.W. The four epidemiological stages in the global evolution of inflammatory bowel disease.Nat. Rev. Gastroenterol. Hepatol. 2021; 18: 56-66Crossref PubMed Scopus (311) Google Scholar. The major forms of IBD include Crohn’s disease (CD) and ulcerative colitis (UC)1Chang J.T. Pathophysiology of inflammatory bowel diseases.N. Engl. J. Med. 2020; 383: 2652-2664Crossref PubMed Scopus (326) Google Scholar. CD is characterized by patchy, transmural inflammation that can manifest anywhere in the gastrointestinal tract, whereas UC is limited to the colonic mucosa and submucosa1Chang J.T. Pathophysiology of inflammatory bowel diseases.N. Engl. J. Med. 2020; 383: 2652-2664Crossref PubMed Scopus (326) Google Scholar. CD and UC are progressive diseases, with chronic inflammation driving the development of complications such as fibrosis, stenosis, abscesses, and colitis-associated colon cancer1Chang J.T. Pathophysiology of inflammatory bowel diseases.N. Engl. J. Med. 2020; 383: 2652-2664Crossref PubMed Scopus (326) Google Scholar, 3Krugliak Cleveland N. Torres J. Rubin D.T. What does disease progression look like in ulcerative colitis, and how might it be prevented?.Gastroenterology. 2022; 162: 1396-1408Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar. Although the precise etiology of IBD is unknown, it involves multiple elements, such as genetic susceptibility, environmental factors (including diet), and the composition of the intestinal microbiome1Chang J.T. Pathophysiology of inflammatory bowel diseases.N. Engl. J. Med. 2020; 383: 2652-2664Crossref PubMed Scopus (326) Google Scholar. The complex interplay among these factors disturbs gut homeostasis, impairs intestinal barrier function, and allows the translocation of commensal microbes and luminal antigens into the immunologically rich lamina propria. Indeed, decreased microbial diversity and increased intestinal permeability are reported to precede the development of IBD4Torres J. Ungaro R.C. Colombel J.F. Is prevention the best way to modify inflammatory bowel disease? How close are we?.Gastroenterology. 2022; 162: 1452-1455Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar. Upon exposure to the luminal contents, innate and adaptive immune cells initiate an inflammatory cascade that leads to the production of cytokines and chemokines involved in immune cell recruitment, differentiation, and activation. Trafficking of immune cells to the gut amplifies the local immune response and drives intestinal inflammation. In healthy hosts, this inflammatory immune response is self-limiting and is resolved by regulatory responses once potential pathogens have been cleared. However, in IBD, a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is sustained by enhanced immune cell priming and the ongoing recruitment of immune cells to the gut5Neurath M.F. Targeting immune cell circuits and trafficking in inflammatory bowel disease.Nat. Immunol. 2019; 20: 970-979Crossref PubMed Scopus (302) Google Scholar. The controlled trafficking of immune cells into the intestinal mucosa plays an essential role in gut homeostasis and immunosurveillance6Zundler S. Becker E. Schulze L.L. Neurath M.F. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances.Gut. 2019; 68: 1688-1700Crossref PubMed Scopus (73) Google Scholar, 7Carman C.V. Martinelli R.T. Lymphocyte-endothelial interactions: emerging understanding of trafficking and antigen-specific immunity.Front. Immunol. 2015; 6: 603Crossref PubMed Scopus (0) Google Scholar. Immune cell migration into peripheral tissues is a multi-step process that begins with rolling adhesion when selectins on the surface of immune cells bind reversibly to their corresponding ligands on the endothelium6Zundler S. Becker E. Schulze L.L. Neurath M.F. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances.Gut. 2019; 68: 1688-1700Crossref PubMed Scopus (73) Google Scholar. These interactions cannot anchor cells against the shearing force of blood flow; therefore, cells appear to roll along the endothelium. Rolling adhesion facilitates the formation of tight binding by exposing immune cells to tissue-specific mediators, such as chemokines, and supporting integrin-dependent arrest. Chemokines secreted by tissue-resident cells bind to specific receptors on the immune cell, triggering a conformational change of integrins. This stabilizes the interactions among integrins on the surface of immune cells and adhesion molecules expressed by endothelial cells, eventually resulting in firm adhesion and extravasation, when the immune cell traverses the endothelial barrier to enter the sub-endothelial tissue. Lastly, immune cells migrate through the tissue under the influence of chemokine or other chemoattractant gradients. The expression profile of chemokine receptors, integrins, and their ligands forms a “zip code” that directs the localization of immune cells6Zundler S. Becker E. Schulze L.L. Neurath M.F. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances.Gut. 2019; 68: 1688-1700Crossref PubMed Scopus (73) Google Scholar. In the intestine, secondary lymphoid organs comprise the draining mesenteric lymph nodes and the gut-associated lymphoid tissue (GALT). The GALT represents key antigen sampling and adaptive immune priming sites in the intestinal wall and includes Peyer’s patches and isolated lymphoid follicles8Mörbe U.M. et al.Human gut-associated lymphoid tissues (GALT); diversity, structure, and function.Mucosal Immunol. 2021; 14: 793-802Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. Peyer’s patches are found throughout the small intestine, with the greatest density in the terminal ileum, and are overlaid with a follicle-associated epithelium rich in specialized antigen-sampling epithelial cells as cells which a process as to and luminal antigens to the can be to adaptive immune U.M. et al.Human gut-associated lymphoid tissues (GALT); diversity, structure, and function.Mucosal Immunol. 2021; 14: 793-802Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. cells of and integrins, and chemokine to facilitate trafficking to the et al.Human mucosal cell adhesion is expressed in intestinal and lymphoid J. 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