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.

• Authors: Giulia Calenda, Rassamon Keawvichit, Géraldine Arrode-Brusés, Kovit Pattanapanyasat, Ines Frank, Siddappa N Byrareddy, James Arthos, Claudia Cicala, Brooke Grasperge, James L Blanchard, Agegnehu Gettie, Keith A Reimann, Aftab A Ansari, Elena Martinelli
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 2 Pg. 810-820 (01 15 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29196458 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Integrins
• Receptors, CCR6
• integrin alpha4beta7

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Dendritic Cells (immunology, metabolism)
• Female
• Integrins (antagonists & inhibitors)
• Lymphocyte Count
• Lymphocyte Subsets (immunology, metabolism)
• Macaca mulatta
• Mucous Membrane (immunology, metabolism)
• Organ Specificity (immunology)
• Receptors, CCR6 (metabolism)