Tu1295 Effect of Vedolizumab on Circulating Lymphocyte Subsets in IBD

Background: Vedolizumab-mediated blockade of integrin alpha 4/beta 7 on the surface of circulating lymphocytes prevents their trafficking to the intestinal mucosa, and has recently been approved as a therapy for IBD. The effect of such disrupted trafficking on immune cell subset frequencies and the kinetics with which such cells lose this blockade are not known. Methods: Blood from nine patients with IBD was obtained prior to and serially after starting vedolizumab. Thawed lymphocytes from these samples were stained with antibody panels to quantify the frequency of lymphocyte subsets over time. An aliquot of these cells were also stained with labeled vedolizumab, with or without cold competition from unlabeled vedolizumab, to determine the kinetics with which immune cell subsets lose integrin blockade after each dose of vedolizumab. Results: By paired analyses, vedolizumab caused a small but significant increase in the naive (CD45RA+, CCR7+) fraction of CD4+ T cells present in the blood, while reducing the fraction of CD4+ T cells expressing the Th17 marker CD161 and decreasing an IgD+, CD27+ fraction of B cells. Fewer naive cells and more CD45RA-/CCR7effector/memory CD4+ T cells (particularly CD161+ T cells contained therein) expressed integrin alpha 4/beta 7 after vedolizumab exposure. All lymphocyte populations demonstrated rapid and dramatic blockade of integrin alpha 4/beta 7 following vedolizumab exposure, but a small amount of blockade was lost fastest in CD161-high CD8+ T cells, resemblingMAIT cells, followed by CD45RA+/CCR7terminal effector memory CD4+ T cells, naive CD8+ T cells, and CD8+ T cells with intermediate CD161 expression. B cells, NK cells and other T cell populations showed negligible loss of integrin blockade between vedolizumab doses. Conclusions: Vedolizumab caused marked integrin alpha 4/ beta 7 blockade in all lymphocyte populations expressing such integrins. This blockade may be lost more quickly by CD161+ and CD45RA+ T cells than other populations. Integrin blockade was associated with increased naive and decreased CD161+ (Th17-like) CD4 T cells in the blood. More of the latter expressed alpha 4/beta 7 after vedolizumab, suggesting that this agent is causing potentially pathogenic , gut-tropic Th17 cells to accumulate in blood, and thus not traffic to the intestinal mucosa to support bowel inflammation.