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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 at the moment. The most advanced is Vedolizumab,8 ,9 an antibody directed at the α4β7 heterodimer, and other antibodies targeting MAdCAM-1 (PF-00547,659)10 or the β7 chain (Etrolizumab)11 are in earlier phases of their clinical development. These intestinal-specific approaches are predicted to be devoid of the risk of PML as an adverse effect, and safety data available so far are in support of this view.8 ,9 The most compelling evidence for a role of intestinal-specific integrin blockade in IBD comes from results of phase III clinical trials of Vedolizumab.8 Vedolizumab proved remarkably effective both in induction and in maintenance of remission in UC. At week 6 of the induction regimen, 47.1% of patients on Vedolizumab compared with 25.5% on placebo showed a clinical response, with 16.9% compared with 5.4% already exhibiting clinical remission at that time point; similarly, maintenance treatment with 4-weekly Vedolizumab resulted in 44.8% of patients being in remission at the 52-week time point compared with 15.9% on placebo.8 The results from the Crohn's disease trial were also very encouraging.9 Although the primary endpoint of clinical remission at 6 weeks was not reached, there were significantly more patients on Vedolizumab in clinical remission at this time point compared with placebo-treated patients.9 Among those patients who had achieved a clinical response to induction therapy, 39% on 8-weekly Vedolizumab, 36.4% on 4-weekly Vedolizumab and 21.6% on placebo were in clinical remission at week 52.9
From a clinical–therapeutic point of view, strategies targeting the intestine-specific α4β7 integrin are being perceived as specific for the recruitment of T lymphocytes; however, they are not. A paper by Mora and colleagues elegantly highlights that α4β7 integrins have important roles in innate immune cells as well, and that α4β7 is required to mediate an important tolerogenic function of the mucosal immune system.4 While blockade of α4β7 integrin in immunodeficient, lymphopenic mice transferred with CD45RBhigh T cells has previously been shown to prevent colitis,12 transfer of CD45RBhigh T cells into hosts that genetically lack β7 integrin surprisingly accelerated colitis,4 implying a protective role of this gut-homing integrin in the innate immune system. Notably, in a series of elegant competitive reconstitution experiments, the authors demonstrated that β7 expression on bone marrow precursors was required to locate tolerogenic CD11c DCs, identified by their capacity to metabolise vitamin A as identified by the ALDEfluor assay, in Peyer's patches, small intestinal lamina propria and mesenteric lymph nodes, but β7 was surprisingly not required for colonic DC reconstitution.4 The authors were able to delineate a LinnegLy6Clow population of bone marrow cells that expressed α4β7 integrin, and which gave rise to a DC population with the capacity to produce RA, required for imprinting the gut-homing characteristics on T cells3 ,4 (figure 1). Interestingly, RA was also required for the generation of these α4β7 +LinnegLy6Clow bone marrow precursor cells, albeit it is not yet known what cellular source of RA within the bone marrow is required for this function.4 Finally, via the demonstration of interleukin 10 induction in ovalbumin-transgenic T cells, the authors show that β7 integrins on bone marrow precursors are required for the differentiation of gut-associated CD11c DCs with tolerogenic potential.4 Although these insights were generated in mice that genetically lack only the β7 chain of the α4β7 integrin, the case made by the authors is compelling that the functional integrin necessary for this function is indeed the α4β7 heterodimer4; the alternative heterodimer, αEβ7, has not been shown to mediate homing to the intestine, nor do αE knockout mice exhibit a defect in DC numbers or function.4
This article raises several interesting points. First, α4β7 integrin has long been known to be important as an intestinal-homing molecule expressed on the surface of T and B cells.5 However, it appears that the same integrin is important for the recruitment of bone marrow precursor cells that differentiate into tolerogenic, RA-producing DCs characteristic of the intestinal tract.4 While the overall effect of blocking α4β7 integrin in the CD45RBhigh model is clearly beneficial,12 it appears that the absence of this integrin on innate immune cells may have an opposite effect.4 It remains to be determined at what anatomic locale this effect is exerted, since the various reconstitution experiments reported in this article indicate that α4β7 might be particularly important in the small intestine and the mesenteric lymph node, but not in the colonic lamina propria.4
May these discoveries have implications for our understanding of the beneficial effects of therapeutics that target α4β7 integrins? It is interesting that Vedolizumab has been unambiguously effective in UC, both the precursor antibody in a phase II trial,13 as well as now in a recently reported phase III study.8 In contrast, it has been slightly harder for both Vedolizumab9 ,14 and Natalizumab15 ,16 to carve out their therapeutic effect in Crohn's disease. However, the long-term maintenance data for both antibodies may be interpreted in that a sizeable subset of Crohn's disease patients exists that derives a profound long-term benefit.9 ,15 Needless to say, this could be related to various causes, including different kinetics of induction therapy in Crohn's disease compared with UC. However, could this potentially also be related to a more ‘detrimental’ effect of blocking the immigration of tolerogenic α4β7 + bone marrow precursors into the intestinal mucosa in Crohn's disease compared with UC? Would this partially counteract the beneficial effects related to blocking the influx of inflammatory T (and B?) lymphocytes? In a converse argument, would this imply that the tolerogenic role of CD103+ ALDE+ DCs is more prominently engaged in Crohn's disease compared with UC? Or could that—naively—be related to the role of α4β7 + bone marrow precursors in populating the small intestine, but not the colonic mucosa with tolerogenic DCs? At this point, we do not know whether Vedolizumab or Natalizumab blocks the immigration of bone marrow precursors into the intestine, which would then differentiate into tolerogenic DCs. Needless to say, these questions are highly speculative, but deserve further study as we currently know very little of how integrin-blocking therapeutics act in vivo in the inflamed (and uninflamed) human intestine. Unsurprisingly, mechanisms of disease as well as the detailed mechanisms of therapeutic intervention may be more complex than originally conceived.
Contributors AK and SLK prepared the manuscript and figure.
Funding Work in the authors laboratory is supported by the European Research Council (ERC) under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement No. 260961 (AK); the National Institute for Health Research Cambridge Biomedical Research Centre (AK) and the Addenbrooke's Charitable Trust (AK).
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.