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* = Presenting author

P025. Vedolizumab does not affect the suppressive activity of gut-homing T regulatory cells

E.R. Fedyk1, L.-L. Yang1, T. Wyant1, V.J. Kadambi1, 1Millennium Pharmaceuticals, Inc., Cambridge, United States

Background

The alpha4beta7 integrin is a phenotypic marker of memory T lymphocytes that preferentially migrate through the gut. Phenotypically discreet subsets of human gut-homing memory T cells have been identified, including proinflammatory TH17 and anti-inflammatory T regulatory (Treg) cells. The activity of these subsets may influence human gastrointestinal homeostasis and disease. Vedolizumab is an investigational humanised monoclonal antibody that binds to the alpha4beta7 integrin and is being developed for ulcerative colitis and Crohn's disease. We therefore investigated to determine if vedolizumab modulated the activity of human Treg cells.

Methods

Total (CD4+CD25+CD127lowFoxP3+) and gut-homing (alpha4beta7highCD4+CD25+CD127lowFoxP3+) populations of Treg cells were identified by flow cytometry in whole-blood samples from healthy human volunteers (n = 8). Both populations were subsequently isolated to >95% purity from whole blood by immunomagnetic separation and fluorescence-activated cell sorting. Purified human Treg cells were activated by stimulation with anti-CD2, -CD3 and -CD28 beads, and functional activity was assessed by coculturing with responder T cells, activated by prior stimulation with phytohemagglutinin or anti-CD3/CD28 beads. Proliferation of responder cells was measured by flow cytometry. Potential effects of vedolizumab were assessed by coculturing Treg and responder cells with saturating concentrations of vedolizumab.

Results

We identified a subset of gut-homing Treg cells that comprise ∼2–15% of the total Treg cell population found in peripheral blood. We isolated these cells and demonstrated that they exhibit suppressive activity that is typical of Treg cells in vitro. Specifically, a coculture of activated responder T cells with the gut-homing Treg subset inhibited proliferation of responder T cells (ie, suppression of proinflammatory activity by Treg). This suppressive activity was not affected by exposure to vedolizumab; incubation of the gut-homing Treg subset with saturating exposures of vedolizumab did not affect the suppression of responder T cells compared with vehicle control or an isotype control antibody.

Conclusion

There was no effect of vedolizumab on the suppressive activity of the gut-homing subset of this population found in peripheral blood of healthy volunteers. These data indicate that vedolizumab does not affect potential anti-inflammatory activity of human Treg cells residing in the submucosa.