ObjectiveVedolizumab, a monoclonal antibody directed against the integrin heterodimer α4β7, is approved for the treatment of Crohn’s disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control.DesignImmunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy.ResultsVedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4β7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation.ConclusionOur findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD.Trial registration numberNCT02694588

Background and Purpose-Stroke is triggered by several risk factors, including influenza and other respiratory tract infections. However, it is unknown how and in which way influenza infection affects stroke outcome. Methods-We infected mice intranasally with human influenza A (H1N1) virus and occluded the middle cerebral artery to induce ischemic strokes. Infarct volume and intracerebral hemorrhage were determined by histology. To evaluate the integrity of the blood-brain barrier and inflammation, we measured various cytokines in vivo and in vitro and performed immunohistochemistry of leukocyte markers, collagen IV, immunoglobulins, and matrix metalloproteinase-9. Results-Influenza virus infection increased infarct size. Whereas changes in cardiovascular parameters did not explain this effect, we found evidence for an inflammatory mechanism. In influenza virus infection, the respiratory tract released cytokines into the blood, such as RANTES that induced macrophage inflammatory protein-2 and other inflammatory mediators in the ischemic brain. In infected mice, there was an increased number of neutrophils expressing the matrix metalloproteinase-9 in the ischemic brain. This was accompanied by severe disruption of the blood-brain barrier and an increased rate of intracerebral hemorrhages after tissue plasminogen activator treatment. To investigate the role of cytokines, we blocked cytokine release by using GTS-21, a selective agonist of the ␣7 nicotinic acetylcholine receptor. GTS-21 ameliorated ischemic brain damage and improved survival. Key Words: ␣7 nicotinic acetylcholine receptor Ⅲ cytokines Ⅲ influenza Ⅲ RANTES Ⅲ stroke S troke is a serious health problem that kills millions of people every year. Several risk factors, including influenza A virus infection, trigger stroke. It has been shown that seasonal variation in stroke incidence closely resembles the occurrence of respiratory tract and influenza virus infections. 1 Furthermore, patients with stroke have an increased rate of preceding respiratory tract infections 2,3 and conversely respiratory tract infections are followed by an increased stroke risk. 4 The interval between symptoms of respiratory tract infection and stroke is often approximately 3 days. 4 Moreover, influenza vaccination has been shown to reduce stroke risk 5,6 and stroke mortality. 7 If influenza triggers stroke, what is the effect of concomitant influenza on the pathogenic cascade leading from cerebral ischemia to tissue demise? Although hard to answer from clinical data, this question is of great importance for the treatment of stroke. Experimental studies have shown that systemic inflammation due to lipopolysaccharides may aggravate neuroinflammation in cerebral ischemia, 8 but the effect of a more naturalistic source of inflammation is unknown. In general, the interplay between systemic inflammation and stroke pathophysiology is highly relevant because stroke often occurs in a pre-existing state of inflammation due to atherosclerosis, obesity, or infection. 9 Previous preclinical...

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