Integrin α4β7 Blockade Preferentially Impacts CCR6+ Lymphocyte Subsets in Blood and Mucosal Tissues of Naive Rhesus Macaques

Abstract

Infusion of a simianized anti-α₄β₇ mAb (Rh-α₄β₇) just before and following SIV infection protected rhesus macaques from developing AIDS and partially from vaginal SIV acquisition. Recently, short-term treatment with Rh-α₄β₇ in combination with cART was found to lead to prolonged viral suppression after withdrawal of all therapeutic interventions. The humanized form of Rh-α₄β₇, vedolizumab, is a highly effective treatment for inflammatory bowel disease. To clarify the mechanism of action of Rh-α₄β₇, naive macaques were infused with Rh-α₄β₇ and sampled in blood and tissues before and after treatment to monitor several immune cell subsets. In blood, Rh-α₄β₇ increased the CD4⁺ and CD8⁺ T cell counts, but not B cell counts, and preferentially increased CCR6⁺ subsets while decreasing CD103⁺ and CD69⁺ lymphocytes. In mucosal tissues, surprisingly, Rh-α₄β₇ did not impact integrin α₄⁺ cells, but decreased the frequencies of CCR6⁺ and CD69⁺ CD4⁺ T cells and, in the gut, Rh-α₄β₇ transiently decreased the frequency of memory and IgA⁺ B cells. In summary, even in the absence of inflammation, Rh-α₄β₇ impacted selected immune cell subsets in different tissues. These data provide new insights into the mechanisms by which Rh-α₄β₇ may mediate its effect in SIV-infected macaques with implications for understanding the effect of treatment with vedolizumab in patients with inflammatory bowel disease.