Impaired Accumulation of Antigen-Specific CD8 Lymphocytes in Chemokine CCL25-Deficient Intestinal Epithelium and Lamina Propria

Wurbel, Marc‐André; Malissen, Marie; Guy‐Grand, Delphine; Malissen, Bernard; Campbell, James J.

doi:10.4049/jimmunol.178.12.7598

Cited by 84 publications

(96 citation statements)

References 30 publications

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“…CCR9 is important for the attraction of these cells to the lamina propria. In contrast, homing of CD4 + T-cells to the lamina propria of the small intestine seems to be less dependent on CCR9 [169,170,171,172]. In a mouse model of colitis, the sites of inflammation coincide with the with the location of CCL25 expression and the number of CCR9 + T-cells increases with disease progression reaching a peak at the time point when most severe inflammation can be observed [173].…”

Section: Anti-c-c Chemokine Receptor Type 9 (Ccr9)mentioning

confidence: 99%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

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Section: Anti-c-c Chemokine Receptor Type 9 (Ccr9)mentioning

confidence: 99%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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“…26 CCR9 and its ligand have been shown to play a key role in the regulation of lymphocyte homing to the small intestine, 27 in particular recruitment of CD8ab þ T cells to the epithelium. 28 Clinical studies have also shown increased numbers of CCR9 þ lymphocytes in the peripheral blood of patients with small bowel CD 29 in addition to the increased production of inflammatory cytokines (e.g., IFN-c and IL-17) by CCR9 þ lymphocytes derived from the mesenteric lymph nodes of these patients. 30 With regard to b7 integrins, the a4b7 heterodimer plays a key role in T-cell migration to the lamina propria, whereas the integrin aEb7, expressed by IELs, 31 binds E-cadherin and is involved in the retention of T effector cells in the epithelial compartment.…”

Section: Intraepithelial Lymphocytesmentioning

confidence: 99%

Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

Henderson

Limbergen

Schwarze

et al. 2011

Inflammatory Bowel Diseases

107

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The intestinal epithelium not only acts as a physical barrier to commensal bacteria and foreign antigens but is also actively involved in antigen processing and immune cell regulation. The inflammatory bowel diseases (IBDs) are characterized by inflammation at this mucosal surface with well-recognized defects in barrier and secretory function. In addition to this, defects in intraepithelial lymphocytes, chemokine receptors, and pattern recognition receptors promote an abnormal immune response, with increased differentiation of proinflammatory cells and a dysregulated relationship with professional antigen-presenting cells. This review focuses on recent developments in the structure of the epithelium, including a detailed account of the apical junctional complex in addition to the role of the enterocyte in antigen recognition, uptake, processing, and presentation. Recently described cytokines such as interleukin-22 and interleukin-31 are highlighted as is the dysregulation of chemokines and secretory IgA in IBD. Finally, the effect of the intestinal epithelial cell on T effector cell proliferation and differentiation are examined in the context of IBD with particular focus on T regulatory cells and the two-way interaction between the intestinal epithelial cell and certain immune cell populations.

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“…In fact, it is known that mice that are genetically deficient for the integrin b 7 , or express a mutated b 7 chain that keeps the a 4 b 7 heterodimer in a persistently adhesive conformation, display fewer intestinal lymphocytes than do control mice (31,49). In addition, fewer IgA ASCs and intraepithelial T cells have also been observed in the small intestine of Ccr9 2/2 or Ccl25 2/2 mice (16,17,19,21). However, some of the …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, lymphocytes destined to home to the small intestine also express the CCR9 receptor for the chemokine CCL25. This chemokine is expressed by crypt epithelial and endothelial cells in the small intestine, where it plays an important role in the recruitment of T cells and IgA ASCs, but not in the colon or other mucosal tissues (13)(14)(15)(16)(17)(18)(19)(20)(21).…”

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confidence: 99%

Intrarectal Immunization and IgA Antibody-Secreting Cell Homing to the Small Intestine

Agnello

Denimal

Lavaux

et al. 2013

The Journal of Immunology

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According to the current paradigm, lymphocyte homing to the small intestine requires the expression of two tissue-specific homing receptors, the integrin α4β7 and the CCL25 receptor CCR9. In this study, we investigated the organ distribution and the homing molecule expression of IgA Ab-secreting cells (ASCs) induced by intrarectal immunization with a particulate Ag, in comparison with other mucosal immunization routes. Intrarectal immunization induces gut-homing IgA ASCs that localize not only in the colon but also in the small intestine, although they are not responsive to CCL25, unlike IgA ASCs induced by oral immunization. The mucosal epithelial chemokine CCL28, known to attract all IgA ASCs, does not compensate for the lack of CCL25 responsiveness, because the number of Ag-specific cells is not decreased in the gut of CCR10-deficient mice immunized by the intrarectal route. However, Ag-specific IgA ASCs induced by intrarectal immunization express the integrin α4β7, and their number is considerably decreased in the gut of β7-deficient mice immunized by the intrarectal route, indicating that α4β7 enables these cells to migrate into the small intestine, even without CCL25 responsiveness. In contrast, IgA ASCs induced by intranasal immunization express low α4β7 levels and are usually excluded from the gut. Paradoxically, after intranasal immunization, Ag-specific IgA ASCs are significantly increased in the small intestine of β7-deficient mice, demonstrating that lymphocyte homing is a competitive process and that integrin α4β7 determines not only the intestinal tropism of IgA ASCs elicited in GALTs but also the intestinal exclusion of lymphocytes primed in other inductive sites.

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Impaired Accumulation of Antigen-Specific CD8 Lymphocytes in Chemokine CCL25-Deficient Intestinal Epithelium and Lamina Propria

Cited by 84 publications

References 30 publications

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

Intrarectal Immunization and IgA Antibody-Secreting Cell Homing to the Small Intestine

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