β7 Integrin Inhibition Can Increase Intestinal Inflammation by Impairing Homing of CD25hiFoxP3+ Regulatory T Cells.

Background & aimsIntegrin α4β7 mediates lymphocyte trafficking to the gut and gut-associated lymphoid tissues, a process critical for recruitment of effector lymphocytes from the circulation to the gut mucosa in inflammatory bowel disease (IBD) and murine models of intestinal inflammation. Antibody blockade of β7 integrins generally is efficacious in IBD; however, some patients fail to respond, and a few patients can experience exacerbations. This study examined the effects of loss of β7 integrin function in murine models of IBD.MethodsIn a mouse IBD model caused by lack of interleukin 10, a cytokine important in CD25hiFoxP3+ regulatory T cell (Treg) function, genetic deletion of β7 integrin or antibody blockade of α4β7-mucosal addressin cell adhesion molecule-1 interaction paradoxically exacerbated colitis.ResultsLoss of β7 impaired the capacity of Tregs homing to the gut and therefore suppress intestinal inflammation in an adoptive T-cell transfer model; however, the intrinsic suppressive function of β7-deficient Tregs remained intact, indicating that the β7 deficiency selectively impacts gut homing. Deletion of β7 integrin did not worsen colitis in an acute dextran sodium sulfate model in which Treg number and function were normal.ConclusionsIn Integrin subunit beta (Itgb)7-/-Il10-/- mice, loss of β7-dependent Treg homing to gut-associated lymphoid tissues combined with loss of intrinsic Treg function exacerbated intestinal inflammation. These results suggest that IBD patients with reduced CD25hiFoxP3+ Treg numbers or function or lack of interleukin 10 could be at risk for failure of α4β7 blocking therapy

The Role of Integrin Beta7 on T Lymphocytes Trafficking during Intestinal Inflammation

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract including two major categories, Crohn’s disease (CD) and ulcerative colitis (UC). Rapid recruitment of lymphocytes from peripheral circulation to the gut mucosa is a key feature of IBD. The process of lymphocytes homing to the gut is a multiple-step adhesionviiicascade that is mediated by adhesion molecules such as integrin α4β7. Integrin α4β7 is expressed on lymphocytes and interacts with its ligand, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which is primarily expressed in the high endothelial venules in the small intestine, the colon, and Peyer’s Patches. Integrin α4β7 is a therapeutic target in IBD. Clinical studies report that vedolizumab, a humanized antibody against integrin α4β7, effectively maintains clinical remission in IBD patients. However, aggravated colitis was observed in a small percentage of patients treated with high dose of vedolizumab, which is probably due to aberrant innate immune response to intestinal mucosal injury and infection. Here, the role of integrin β7 on recruiting conventional and regulatory T lymphocytes during intestinal inflammation is further investigated by using two IBD mouse models. Conventional/effector T cells activate other effector immune cells whereas regulatory T cells suppress inflammatory activities and maintain peripheral tolerance. The results demonstrated that deficiency in integrin β7 exacerbates induced spontaneous colitis. The suppression function of β7-deficient Treg cells remains intact. However, integrin β7-deficiency impairs the homing capacity of both regulatory T cells and effector T cells to the GALT. These findings possibly explain the adverse effects seen in high dose vedolizumab treatment, suggesting that excessive blocking of integrin β7 function should be avoided to prevent potential adverse effects of this medication

The Role of Integrin Beta7 on T Lymphocytes Trafficking during Intestinal Inflammation

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract including two major categories, Crohn’s disease (CD) and ulcerative colitis (UC). Rapid recruitment of lymphocytes from peripheral circulation to the gut mucosa is a key feature of IBD. The process of lymphocytes homing to the gut is a multiple-step adhesionviiicascade that is mediated by adhesion molecules such as integrin α4β7. Integrin α4β7 is expressed on lymphocytes and interacts with its ligand, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which is primarily expressed in the high endothelial venules in the small intestine, the colon, and Peyer’s Patches. Integrin α4β7 is a therapeutic target in IBD. Clinical studies report that vedolizumab, a humanized antibody against integrin α4β7, effectively maintains clinical remission in IBD patients. However, aggravated colitis was observed in a small percentage of patients treated with high dose of vedolizumab, which is probably due to aberrant innate immune response to intestinal mucosal injury and infection. Here, the role of integrin β7 on recruiting conventional and regulatory T lymphocytes during intestinal inflammation is further investigated by using two IBD mouse models. Conventional/effector T cells activate other effector immune cells whereas regulatory T cells suppress inflammatory activities and maintain peripheral tolerance. The results demonstrated that deficiency in integrin β7 exacerbates induced spontaneous colitis. The suppression function of β7-deficient Treg cells remains intact. However, integrin β7-deficiency impairs the homing capacity of both regulatory T cells and effector T cells to the GALT. These findings possibly explain the adverse effects seen in high dose vedolizumab treatment, suggesting that excessive blocking of integrin β7 function should be avoided to prevent potential adverse effects of this medication