α4β7integrin: beyond T cell trafficking

Integrins and chemokines are critical for immune cell recruitment to tissue under homeostatic and pathological conditions.1 The heterodimeric integrin α4β7, expressed on T cells, specifies the recruitment of T cells to the intestinal mucosa upon its interaction with its ligand MAdCAM-1.1 Intestinal specificity is imprinted in T cells via upregulation of α4β7 integrin upon their interaction with CD103 dendritic cells (DCs) in the mesenteric lymph node when their cognate antigen is being presented by the major histocompatibility complex.2 The vitamin A metabolite retinoic acid (RA), produced by CD103 DCs via the enzyme retinaldehyde dehydrogenase 2 (encoded by Aldh1a2 gene), acting on T cells plays a critical role in this intestinal imprinting,3 and DCs with this capacity can be identified by an assay that detects this enzymatic activity (ALDE+).4 Pharmacological intervention in tissue-specific recruitment of T cells has the potential advantage of very precise therapeutic intervention at the site of inflammation.5 This theoretical promise that stemmed from fundamental work and preclinical model systems was indeed upheld. Blockade of the brain-specific localisation signal α4β1 via the anti-α4 antibody Natalizumab is among the most potent therapeutics currently available for multiple sclerosis, while the same antibody that similarly blocks the intestinal-specific α4β7 integrin also demonstrated efficacy in active Crohn's disease.6 However, due to its uncommon, but detrimental adverse effect of reactivating infection with JC virus which may lead to progressive multifocal leukoencephalopathy (PML),7 Natalizumab received only limited marketing approval for Crohn's disease in specific jurisdictions. However, more precise approaches, which are indeed specific for the intestinal tract but should leave leucocyte recruitment to the brain and other organs intact, have been developed and are at different stages of clinical development …