Α4β7 Integrin Research Articles

Vedolizumab in the treatment of inflammatory bowel diseases: whom and how?

The article is devoted to the use of vedolizumab, an α4β7 integrin antagonist, in the treatment of inflammatory bowel diseases (ulcerative colitis and Crohn’s disease). It presents the results of clinical trials of the drug and the experience of using vedolizumab in actual clinical practice. The latest available information about the drug’s safety profile is provided. The authors considered the practical aspects of therapy, such as determining the indications for treatment, tactics in loss of response, the need for a combination of vedolizumab with immunosuppressors, and the use of the drug in specific categories of patients.

Gut check for a promising HIV treatment

HIV Eradicating HIV in infected patients likely requires disrupting the reservoir of infected T cells in the gastrointestinal tract. One approach may be targeting cells expressing the integrin α4β7, which has been tested in simian immunodeficiency virus models and is an approved therapy for inflammatory bowel disease. Uzzan et al. studied a small cohort of HIV-infected individuals on antiretroviral therapy who began receiving an antibody against α4β7 as a treatment for their mild inflammatory bowel disease. Longitudinal colonoscopies revealed that the anti-α4β7 therapy disrupted local lymphoid aggregates. The treatment was well tolerated, but long-term effects on the HIV reservoir remain to be determined. Sci. Transl. Med. 10 , eaau4711 (2018).

PGI4 - REAL-WORLD TRENDS IN CLINICAL CHARACTERISTICS OF INFLAMMATORY BOWEL DISEASE (IBD) PATIENTS INITIATING VEDOLIZUMAB OVER TIME IN ISRAEL

Vedolizumab (VDZ), a gut-selective humanized monoclonal antibody binding to α4β7 integrin, is approved for the treatment of patients with moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD). This study aimed to characterize IBD patients initiating VDZ over time in Israel, from launch (2015). A retrospective cohort study was performed in Maccabi Healthcare Services, a 2-million-member health plan in Israel. Included were patients diagnosed with UC or CD with ≥1 dispensed VDZ in 2015-2017 (index date was defined as first purchase), with ≥12 months’ pre-index health plan enrolment. Baseline socio-demographic, comorbidity, pharmacy, surgery, hospitalization and laboratory data were described at VDZ initiation and compared across index calendar years using Chi-squared and Kruskal-Wallis tests. The cohort included 421 patients initiating VDZ in 2015 (n=94), 2016 (n=141) and 2017 (n=186). VDZ was initiated after a median (IQR) of 7.8 (3.9-13.1) and 6.0 (2.1-13.8) years since CD (n=242) and UC (n=178) diagnosis, respectively. From 2015 to 2017, there was a trend towards initiating VDZ sooner after IBD diagnosis (median [IQR]: 9.0 [4.3-14.4] to 6.8 [2.5-13.1] years; P=0.217), increasing age of VDZ patients (mean ±SD: 36.5±15.5 to 41.4±17.8 years; P=0.050) and percentage of males (43.6% to 54.8%; P=0.148). The proportion of biologic-naïve patients initiating VDZ increased significantly (P<0.001) over time (2015, 2016, 2017) in CD (5.4%, 11.0%, 26.5%) and UC (13.2%, 33.8%, 49.3%) patients. Prior use of immunomudulators (IMM) also declined significantly from 2015 to 2017 overall (P=0.001) and among CD (96.4% to 82.3%) and UC (97.4% to 78.1%) patients. Overall baseline IBD-related surgery rates declined significantly (P=0.014) over time: 26.6% (2015); 12.8% (2016); 15.1% (2017). Since launch, VDZ utilization increased in biologic-naïve and IMM-naïve IBD patients and there was a trend to use VDZ earlier in the disease course. Further analyses are planned to assess real-world outcomes in this cohort.

β7 integrins contribute to intestinal tumor growth in mice.

The gut homing receptor integrin α4β7 is essential for the migration of pro-inflammatory T cells into the gut mucosa. Since intestinal neoplasia has been associated with chronic inflammation, we investigated whether interfering with gut-homing affects intestinal tumorigenesis. Using chemically induced and spontaneous intestinal tumor models we showed that lack of β7 integrin significantly impairs tumor growth without affecting tumor frequencies, with a mild translatable effect on overall survival. This correlates with human data showing lower MAdCAM-1 expression and disease-free survival in colorectal cancer patients. Thus, paradoxically in contrast to extra-intestinal tumors, blocking migration of immune cells into the gut might have a positive therapeutic effect on intestinal neoplasia.

Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease.

Vedolizumab (VDZ) blocks α4β7 integrin and is licenced for the treatment of IBD. It has been associated with mild SpA-related features, including sacroiliitis and synovitis. Herein we report a series of cases demonstrating the emergence of severe SpA-associated enthesitis/osteitis following successful IBD therapy with VDZ. We evaluated 11 VDZ-treated patients with IBD across seven centres who developed severe active SpA and/or enthesopathy, with the aim of characterizing the VDZ-associated SpA or entheseal flares. Imaging features demonstrating particularly severe disease were recorded. De novo SpA developed in 9 of 11 patients and flare of known SpA in 2 patients, with 4 patients requiring hospitalization due to disease severity. Available data showed that one of seven cases were HLA-B27 positive. The median time from VDZ initiation to flare was 12 weeks, with IBD well controlled in 7 of 10 patients (no data for 1 patient) at flare. Severe SpA enthesitis/osteitis was evident on MRI or US, including acute sacroiliitis (n = 5), extensive vertebral osteitis (n = 1), peri-facetal oedema (n = 1) and isolated peripheral enthesitis (n = 3). Due to arthritis severity, VDZ was discontinued in 9 of 11 patients and a change in therapy, including alternative anti-TNF, was initiated. Severe SpA, predominantly HLA-B27 negative, with osteitis/enthesitis may occur under successful VDZ treatment for IBD, including in subjects with prior anti-TNF therapy for intestinal disease.

Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7.

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7 and a soluble α4β7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4β7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7 binding site, a cryptic epitope that lies 7–9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4β7 interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.

Past, Present and Future of Therapeutic Interventions Targeting Leukocyte Trafficking in Inflammatory Bowel Disease.

Studies in the 1990s using animal models of intestinal inflammation delineated the crucial molecules involved in leukocyte attraction and retention to the inflamed gut and associated lymphoid tissues. The first drug targeting leukocyte trafficking tested in inflammatory bowel diseases was the anti-ICAM-1 antisense oligonucleotide alicaforsen, showing only modest efficacy. Subsequently, the anti-α4 monoclonal antibody natalizumab proved efficacious for induction and maintenance of remission in Crohn's disease, but was associated with progressive multifocal leukoencephalopathy due to its ability to interfere with both α4β1 and α4β7 function. Later developments in this area took advantage of the fairly selective expression of MAdCAM-1 in the digestive organs, showing that vedolizumab, a more specific monoclonal antibody selectively blocking MAdCAM-1 binding to integrin α4β7, was efficacious for induction and maintenance of remission in ulcerative colitis and Crohn's disease, and it was not associated with neurological complications. Currently, other drugs targeting the β7 subunit, immunoglobulin superfamily molecules expressed on the endothelium, as well as blockade of lymphocyte recirculation in lymph nodes through modulation of sphingosine 1-phosphate receptors are under development. The potential use and risks of combined anti-trafficking therapy will be examined in this review.

Real-world clinical, endoscopic and radiographic efficacy of vedolizumab for the treatment of inflammatory bowel disease.

Vedolizumab is an α4β7 integrin antagonist with proven efficacy for inducing and maintaining clinical response and remission in Crohn's disease (CD) and ulcerative colitis (UC). To evaluate clinical and objective response and remission rates with vedolizumab in a large, real world cohort. A retrospective cohort study of adult CD and UC patients receiving vedolizumab between 2012 and 2017 was conducted. clinical or objective response and remission at 3, 6 and 12months after induction. Clinical remission was defined by complete, steroid-free absence of symptoms. Objective remission was defined by endoscopic mucosal healing or normalisation of radiographic appearance on contrast-enhanced ultrasound or CT/MR enterography. The study included 222 vedolizumab patients (122 CD, 100 UC). In CD, clinical remission at 3, 6 and 12months was achieved in 19.8% (22/111), 22.1% (21/95) and 22.1% (15/68) of patients, respectively. Objective remission occurred in 11.5% (6/52), 21.2% (14/66), and 18.9% (7/37) of patients at 3, 6 and 12months, respectively. In UC, clinical remission at 3, 6, and 12months was 51.0% (51/100), 61.8% (55/89) and 61.9% (39/63), respectively. Endoscopic remission occurred in 27.5% (11/40), 41.0% (16/39) and 47.8% (22/46) of patients at 3, 6 and 12months, respectively. In multivariable analysis, patients with UC as compared to CD, and those with milder disease activity were more likely to achieve objectively defined remission at both 6 and 12months. Vedolizumab was effective for induction and maintenance of clinical and objective remission, both in Crohn's disease and ulcerative colitis.

PF-00547659 for the treatment of Crohn’s disease and ulcerative colitis

ABSTRACTIntroduction: Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells.An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD).Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD.Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn’s disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD.

Clinical adverse effects of natalizumab: Protocol for a meta-analysis of randomized double-blind placebo-controlled clinical trails.

Background:Natalizumab (NAT), a humanized monoclonal antibody, which binds in both α4β1 integrins and α4β7 integrins, is approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). An uncommon but serious adverse event from NAT treatment is known as progressive multifocal leukoencephalopathy (PML). However, clinical comprehensive safety evidence of NAT is limited.Methods:We will search Medline, Embase, Cochrane library, and ClinicalTrials.gov website from inception to May 9, 2018. Double-blind, randomized placebo-controlled trials reporting safety data of NAT will be eligible for inclusion. Outcome variables will include adverse events (AEs) varying degrees and AEs occurring in ≥ 5% patients with NAT or placebo. STATA software (version 12, Statacorp, College Station, TX) will be utilized to assess risk of bias and synthesize data. Outcomes will be reported by weight mean difference (WMD), risk ratios (RRs), and their 95% confidence intervals (95% CIs). I2 statistic will be used to evaluate heterogeneity among studies.Results:This systemic review and meta-analysis will evaluate serious AEs and AEs of NAT as compared to placebo.Conclusion:Our study will provide a comprehensive picture of AEs of NAT.

Core-shell nanoparticles for targeted and combination antiretroviral activity in gut-homing T cells

A major sanctuary site for HIV infection is the gut-associated lymphoid tissue (GALT). The α4β7 integrin gut homing receptor is a promising therapeutic target for the virus reservoir because it leads to migration of infected cells to the GALT and facilitates HIV infection. Here, we developed a core-shell nanoparticle incorporating the α4β7 monoclonal antibody (mAb) as a dual-functional ligand for selectively targeting a protease inhibitor (PI) to gut-homing T cells in the GALT while simultaneously blocking HIV infection. Our nanoparticles significantly reduced cytotoxicity of the PI and enhanced its in vitro antiviral activity in combination with α4β7 mAb. We demonstrate targeting function of our nanocarriers in a human T cell line and primary cells isolated from macaque ileum, and observed higher in vivo biodistribution to the murine small intestines where they accumulate in α4β7+ cells. Our LCNP shows the potential to co-deliver ARVs and mAbs for eradicating HIV reservoirs.

Clindamycin Administration Increases the Incidence of Collagen-Induced Arthritis in Mice Through the Prolonged Impact of Gut Immunity.

The profound influence of gut flora on host immune system and its link with autoimmune disorders have been established. However, the role of certain antibiotic in progression of autoimmune disorder is still confusing. Here, we employed a collagen-induced arthritis (CIA) model to explore the role of clindamycin administration in different scenarios. In the first scenario, mice treated with antibiotics for 4weeks were performed with the induction of CIA immediately. The results showed that clindamycin administration promoted the incidence and severity of CIA, while the recipients of vancomycin showed completed tolerance. We also found that increased gut-associated Th1 and Th17 cells might be related to the subsequent expansion of collagen-specific immune response. In the second scenario, mice treated with antibiotics for 4weeks were performed with CIA induction 4weeks later. Notably, clindamycin administration showed a prolonged impact on the incidence and severity of CIA, as well as the gut immunity as compared to vancomycin administration. In addition, antibody depletion of integrin α4β7 systemically resulted in an impaired CIA response, underlining the influence of gut immunity. In the mice that received clindamycin, the abundance of anaerobic bacteria was significantly decreased and showed little recovery at 4weeks later. Our observations highlighted the different characteristics of antibiotic administration on the development of autoimmune disorders and indicated its link with gut immunity.

Vedolizumab for inflammatory bowel disease: From randomized controlled trials to real-life evidence.

The biologic antitumor necrosis factor alpha (anti-TNFα) agents have revolutionised the treatment of inflammatory bowel disease (IBD). However, some patients experience primary nonresponse, loss of response, or intolerance. Therefore, introducing a newer class of therapy with a mechanism of action that acts on different inflammatory pathways involved in IBD pathogenesis is appealing. Vedolizumab is a fully humanised monoclonal antibody that selectively targets α4β7 integrin. Based on the results of the pivotal clinical GEMINI trials, vedolizumab was approved for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD) refractory or intolerant to either conventional therapy or TNFα inhibitors. This review describes the efficacy, safety, and tolerability of vedolizumab reported in both randomized, controlled, clinical trials and from real-world experience in patients with UC and CD in order to identify its place in treatment algorithms for IBD.

Development of Endocyclic Control Elements for Peptide Macrocycles.

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α4β7 integrin antagonist.

Soluble Mucosal Addressin Cell Adhesion Molecule 1 and Retinoic Acid are Potential Tools for Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Treated with Vedolizumab: A Proof of Concept Study.

Vedolizumab [VDZ], a humanized monoclonal antibody targeting α4β7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease [IBD] who have not adequately responded to standard therapies, and high vedolizumab trough levels [VTLs] have been associated with clinical remission. The α4β7 integrin binds to endothelial MAdCAM-1 and is upregulated by retinoic acid [RA]. The aim of this study was to determine the relationships between soluble MAdCAM-1 [sMAdCAM-1] and RA concentrations during clinical remission with VDZ maintenance therapy. In a retrospective study performed in IBD patients treated with VDZ, we measured VTL, sMAdCAM-1 and RA concentrations. Among the 62 included patients [38 Crohn's disease], 24 relapsed and 38 stayed in remission from Weeks 10 to 30 after VDZ initiation. During this maintenance therapy, the median values of VTLs and RA were 15.4 µg/mL and 0.97 ng/mL, respectively, whereas sMAdCAM-1 was undetectable [<0.41 ng/mL] in 67.3% of samples. The positive predictive value [PPV] of undetectable sMAdCAM-1 for clinical remission was 80.0%, with a corresponding sensitivity of 74.6%. On multivariate analysis, undetectable sMAdCAM-1 and high VTLs [>19 µg/mL] were independently associated with clinical remission [OR = 7.5, p = 0.006 and OR = 2.2, p = 0.045, respectively]. The combination of sMAdCAM-1 < 0.41 ng/mL and VTL > 19 µg/mL was the best pharmacokinetic profile, with a PPV of 95.2%. Median values of sMAdCAM-1 and RA were significantly higher [p = 0.0001] before VDZ therapy than during the follow-up [sMAdCAM-1: 40.5 vs < 0.41 ng/mL; RA: 1.7 vs 0.97 ng/mL]. Only RA > 1.86 ng/mL before VDZ therapy was predictive of clinical remission during the follow-up (Area Under a Receiver Operating Characteristic curve [AUROC] = 80.7%). Undetectable sMAdCAM-1 appears strongly associated with clinical remission during VDZ maintenance therapy. Combination of undetectable sMAdCAM-1 with high VTL is also potentially interesting for therapeutic drug monitoring. Baseline RA concentrations are predictive of clinical remission. These findings need to be confirmed in further prospective studies.

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease.

ObjectiveAnti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn’s disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.DesignMucosal and blood cells were isolated from patients with Crohn’s disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.ResultsResponders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R− cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.ConclusionsExpansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn’s disease refractory to anti-TNF therapy.

Rapid Response to Vedolizumab Therapy in Biologic-Naive Patients With Inflammatory Bowel Diseases

Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists. We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (N= 374) or CD (N= 784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2). In patients with UC (overall or naive to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naive to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naive) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naive) of those receiving placebo. Among TNF antagonist-naive patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo). In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. ClinicalTrials.gov no: NCT00783718, NCT00783692, NCT01224171.

Integrin α4β7 switches its ligand specificity via distinct conformer-specific activation.

Chemokine (C-C motif) ligand 25 (CCL25) and C-X-C motif chemokine 10 (CXCL10) induce the ligand-specific activation of integrin α4β7 to mediate the selective adhesion of lymphocytes to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) or vascular cell adhesion molecule-1 (VCAM-1). However, the mechanism underlying the selective binding of different ligands by α4β7 remains obscure. In this study, we demonstrate that CCL25 and CXCL10 induce distinct active conformers of α4β7 with a high affinity for either MAdCAM-1 or VCAM-1. Single-cell force measurements show that CCL25 increases the affinity of α4β7 for MAdCAM-1 but decreases its affinity for VCAM-1, whereas CXCL10 has the opposite effect. Structurally, CCL25 induces a more extended active conformation of α4β7 compared with CXCL10-activated integrin. These two distinct intermediate open α4β7 conformers selectively bind to MAdCAM-1 or VCAM-1 by distinguishing their immunoglobulin domain 2. Notably, Mn2+ fully opens α4β7 with a high affinity for both ligands. Thus, integrin α4β7 adopts different active conformations to switch its ligand-binding specificity.

Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines

All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4β7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/β signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.

Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease.

Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between α4β7 and its ligand, mucosal addressin cellular adhesion molecule-1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by αEβ7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease pathobiology. This review will provide an overview of integrin structure, function and signalling, and highlight the role that these molecules play in leukocyte homing and retention. Anti-integrin therapeutics, including gut-selective antibodies against the β7 integrin subunit [etrolizumab] and the α4β7 integrin heterodimer [vedolizumab and abrilumab], and the non-gut selective anti-α4 integrin [natalizumab], will be discussed, as well as novel targeting approaches using small molecules.