Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.

Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.

T Cell Repertoire Homogeneity and Blood-Gut Overlap in Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) causes a marked increase in the number of T cells in the intestinal mucosa. Debate exists about whether these excess cells arise from local clonal proliferation or recruitment from the periphery. METHODS: CD8+ T cells were sorted from colon biopsy specimens and blood for T-cell receptor (TCR) ß-chain sequencing. Biopsy specimens from inflamed or uninflamed colon from ulcerative colitis or Crohn's disease cohorts were compared with colon biopsy specimens from people without IBD, as well as with autologous blood α4ß7+, α4ß7- effector/memory, terminal effector/memory CD45RA+ T cell, and mucosal-associated invariant T-cell CD8 subpopulations. RESULTS: CD8 TCR diversity in mucosa and blood did not correlate with inflammation. Repertoire overlap between any 2 distinct locations of a given person's colon was consistently high, although often lower between inflamed and uninflamed sites. CD8 TCR repertoires overlapped between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4ß7+ T cells. Inflamed tissue consistently overlapped more than uninflamed tissue with each blood subpopulation. CONCLUSIONS: CD8 T-cell clones are spread homogenously throughout the length of the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar TCR diversity in both argues against local clonal expansion being the main source of excess cytotoxic T cells in inflamed mucosa. Rather, the increased TCR overlap observed between blood and inflamed mucosa supports the significance of T-cell trafficking in IBD pathogenesis, particularly concerning α4ß7+ T-cell populations.

Colonic mucosal associated invariant T cells in Crohn's disease have a diverse and non-public T cell receptor beta chain repertoire.

OBJECTIVES: Mucosal-Associated Invariant T (MAIT) cells are T cells with a semi-invariant T cell receptor (TCR), recognizing riboflavin precursors presented by a non-polymorphic MR1 molecule. As these precursors are produced by the gut microbiome, we characterized the frequency, phenotype and clonality of MAIT cells in human colons with and without Crohn's disease (CD). METHODS: The transcriptome of MAIT cells sorted from blood and intestinal lamina propria cells from colectomy recipients were compared with other CD8+ T cells. Colon biopsies from an additional ten CD patients and ten healthy controls (HC) were analyzed by flow cytometry. TCR genes were sequenced from individual MAIT cells from these biopsies and compared with those of MAIT cells from autologous blood. RESULTS: MAIT cells in the blood and colon showed a transcriptome distinct from other CD8 T cells, with more expression of the IL-23 receptor. MAIT cells were enriched in the colons of CD patients, with less NKG2D in inflamed versus uninflamed segments. Regardless of disease, most MAIT cells expressed integrin α4ß7 in the colon but not in the blood, where they were enriched for α4ß7 expression. TCR sequencing revealed heterogeneity in the colon and blood, with few public sequences associated with cohorts. CONCLUSION: MAIT cells are enriched in the colons of CD patients and disproportionately express molecules (IL-23R, integrin α4ß7) targeted by CD therapeutics, to suggest a pathogenic role for them in CD. Public TCR sequences were neither common nor sufficiently restricted to a cohort to suggest protective or pathogenic antigen-specificities.

Vedolizumab Efficacy Is Associated With Decreased Intracolonic Dendritic Cells, Not Memory T Cells.

BACKGROUND: Vedolizumab, an antibody blocking integrin α4ß7, is a safe and effective therapy for Crohn's disease and ulcerative colitis. Blocking α4ß7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. METHODS: We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect of resolving inflammation on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 65 case subjects receiving vedolizumab were matched with biopsies from 65 control individuals, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full messenger RNA transcriptome sequencing of sorted T cells. RESULTS: No difference was seen between vedolizumab recipients and control individuals in the quantity of any antigen-experienced T lymphocyte subset or in the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than control individuals, regardless of response. However, the most striking finding was a marked reduction in CD1c+ (BDCA1+) dendritic cells exclusively in vedolizumab-responsive patients. In blood, these dendritic cells ubiquitously express high levels of α4ß7, which is rapidly downregulated upon vedolizumab exposure. CONCLUSIONS: The clinical effects of vedolizumab reveal integrin α4ß7-dependent dendritic cell migration to the intestinal mucosa to be central to inflammatory bowel disease pathogenesis.

Vedolizumab had no effect on the number or gene expression of memory T lymphocytes in the colons of recipients relative to control individuals. However, the colons of vedolizumab-responsive patients had distinctly fewer dendritic cells, which in blood express the most integrin α4ß7.

Janus kinase inhibitors differentially inhibit specific cytokine signals in the mesenteric lymph node cells of IBD patients.

BACKGROUND: Janus kinase (JAK) inhibitors (JAKinibs) are effective small molecule therapies for treating Crohn's Disease (CD) and Ulcerative Colitis (UC), collectively known as inflammatory bowel disease (IBD). By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signaling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first and second generation JAKinibs display different clinical efficacies in CD and UC. METHODS: We conducted a comparative phosflow study of four JAKinibs (filgotinib, upadacitinib, tofacitinib, and deucravacitinib) to observe subtle mechanistic differences that may dictate their clinical behavior. Resected mesenteric lymph node (MLN) cells from 19 patients (9 CD, 10 UC) were analyzed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs. RESULTS: We found a higher potency of the JAK 1/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signaling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signaling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-ßpathways, albeit more potently than the other JAKinibs . Additionally, we found some differences in the sensitivity of immune cells from CD versus UC and patients with versus without a CD-associated NOD2 polymorphism to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation. CONCLUSIONS: Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families to explain their clinical efficacy.

Characterizing Regionalization of Inflammatory Bowel Disease Hospitalizations and Operations in Washington State.

BACKGROUND: Hospitalizations for inflammatory bowel disease (IBD) are a major contributor of healthcare utilization. We assessed IBD hospitalizations and surgical operations in Washington State to characterize regionalization patterns. METHODS: We identified a cohort of hospitalizations for Crohn's disease (CD) or ulcerative colitis (UC) from 2008 to 2019 using Washington State's Comprehensive Hospital Abstract Reporting System (CHARS). Hospitalizations were characterized by emergent or elective acuity and whether an operation or endoscopic procedure was performed. Facility volume and distance travelled by patients were used to determine regionalization. RESULTS: There were 20,494 IBD-related hospitalizations at 95 hospitals: 13,585 (66.3%) with CD and 6,909 (33.7%) with UC. Emergencies accounted for 78.2% of all IBD-related hospitalizations and did not differ between CD (78.3%) and UC (77.9%) (p = 0.54). Surgery was performed during 10.3% and endoscopy during 30.6% of emergent hospitalizations. 72.0% of emergent hospitalizations occurred at 22 facilities, while 71.1% of elective hospitalizations were concentrated at 9 facilities. Operations were performed during 78.5% of elective hospitalizations, and five hospitals performed 69% of all elective surgery. Laparoscopic surgery increased in both emergent (17% to 52%, p < 0.001) and elective operations (18% to 42%, p < 0.001) from 2008 to 2019. CONCLUSIONS: In Washington State, most IBD hospitalizations were emergent, which were decentralized and typically non-operative. By contrast, most elective admissions involved surgery and were centralized at a few high-volume centers. Further understanding the drivers behind IBD hospitalizations may help optimize emergent medical and elective surgical care at a state level.

FOXP3+ regulatory T cells use heparanase to access IL-2 bound to ECM in inflamed tissues.

FOXP3+ regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resource in vivo. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their tolerogenic function in vivo. Together, these data identify novel roles for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.

Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma.

Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employ an unbiased proteogenomic approach to dissect RAS signaling in MM. We discover that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes are more aggressive and enriched in RAS mutations, and we detect interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergizes with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this mode of RAS signaling.

MAdCAM-1 Costimulates T Cells through Integrin α4ß7 to Cause Gene Expression Events Resembling Costimulation through CD28.

Successful treatment of inflammatory bowel disease (IBD) with the anti-integrin α4ß7 mAb vedolizumab suggests that interaction of this integrin with addressin mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is central to IBD pathogenesis. Although this was presumed to be due to an inhibition of lymphocyte trafficking to the gut, as has been observed in animal models, we report no depletion of CD4 T cells from the colonic mucosa as a consequence of vedolizumab treatment in humans, regardless of efficacy. Likewise, no upregulation of alternative trafficking mechanisms was observed as a consequence of therapy to suggest that this homeostasis is maintained in patients by a mechanistic escape from inhibition. Instead, we explore a role for MAdCAM-integrin interaction as a gut-specific costimulatory signal, demonstrating that it can replace CD28 ligation to activate human T cells in vitro. This activation through integrin α4ß7 is mediated through the gut-restricted molecule MAdCAM-1, and it cannot be replicated by matrix molecules or proteins that bind other integrins. A detailed analysis of mRNA expression by human T cell subsets following suboptimal TCR stimulation in the presence or absence of CD28 versus MAdCAM-1 costimulation reveals marked similarity in the effect that these two signals have upon T cells, with temporal or quantitative differences detected in the expression of cytokines associated with Th17 cells or pyogenic inflammation. Thus, we describe an alternative costimulatory pathway for T cells in the intestine, through ligation of integrin α4ß7 by MAdCAM-1, which may explain the therapeutic efficacy of vedolizumab and have implications concerning the treatment of IBD.

Usefulness of Fluoroscopy for Endoscopic Balloon Dilation of Crohn's Disease-Related Strictures.

BACKGROUND: Fluoroscopy is often used for endoscopic balloon dilation (EBD) of Crohn's disease (CD)-related strictures. However, its benefit remains unclear. AIMS: To compare EBD with (EBDF) and without (EBDNF) fluoroscopic guidance in CD patients with strictures. METHODS: Single-center, nested, case-control retrospective study of EBD for CD-related strictures. Technical and clinical success and safety outcomes were compared between EBDF and EBDNF. RESULTS: A total of 122 strictures in 114 CD patients who underwent EBD from 2010 to 2018 at a single institution were reviewed (44 patients EBDF vs. 70 EBDNF). Esophagogastroduodenoscopy was the approach in 8 strictures, colonoscopy in 86, and deep enteroscopy in 28. There were no significant differences in the rates of technical and clinical success, need for repeat dilation and surgery between the two groups, although the mean maximal endoscopic balloon diameter was larger in the EBDNF group (17.1 ± 1.9 vs. 14.1 ± 2.5; p < 0.001). There was one perforation in EBDF and no serious complications in EBDNF. In multivariate analysis, balloon size < 15 mm (odds ratio [OR] 6.388; 95% CI 1.96-20.79; p = 0.002) and multiple strictures (OR 3.897; 95% CI 1.09-14.01; p = 0.037) were associated with repeat EBD, and age < 50 years (OR 7.178; 95% CI 1.38-37.44; p = 0.019) and small bowel (vs. colon) location (OR 7.525; 95% CI 1.51-37.47; p = 0.014) were associated with the need for surgery after EBD. CONCLUSIONS: EBD for CD-related strictures can be performed safely and effectively without fluoroscopic guidance. Balloon size, patient age, stricture location, and multiplicity are associated with clinical success and avoidance of surgery.

Clinical audit comparing radiation dose metrics between WEB and coil embolisation in the treatment of intracranial aneurysms.

INTRODUCTION: Intrasaccular flow disruption is a new and effective endovascular treatment for intracranial aneurysms. While endovascular treatment is a minimally invasive procedure, it does carry a radiation risk. As radiation dose should be kept as low as reasonably achievable (ALARA), the main objective of this study was to analyse KAP (kerma area product), fluoroscopy and procedure time during the treatment of aneurysms treated with coiling and the Woven-EndoBridge (WEB) device. A secondary objective was to look at the reference air kerma (RAK) to determine if the patient receives a dose that could cause tissue effects. METHODS: KAP, fluoroscopy and procedure time were retrospectively analysed in patients who had an aneurysm treatment. Aneurysms with diameters of 4-11mm, over a four-year period, in the anterior and posterior circulation of the brain were analysed in this study. Patients were treated by coiling or WEB. RAK were summed together in the working projection to give an estimated entrance surface dose (ESD) in cases with the highest KAP. RESULTS: A total of 47 aneurysms treated with WEB and 104 aneurysms treated with coiling techniques met the inclusion criteria. The average KAP was 6884.1 ± 2774.4µGym2 with coiling techniques and 5658.7 ± 1602.5µGym2 with WEB (p=0.006; CI =363-2086µGym2). This demonstrates an 18% reduction with WEB. Mean fluoroscopy time for coiling was 63.5 ± 42.6minutes and 33.8 ± 28.8minutes for WEB (p=<0.001; CI=16-43minutes). Fluoroscopy time was reduced by nearly 50% with WEB. On average, there was a 27-minute reduction of procedure time when using WEB compared to coiling. The RAK determined for the working projections did not exceed the 2Gy threshold for tissue effects. CONCLUSION: Treatment of aneurysms using the WEB shows a reduction in KAP, fluoroscopy, and procedure time. This study further demonstrates the benefits of intrasaccular flow disruption for treatment of intracranial aneurysms.

PGD2 and CRTH2 counteract Type 2 cytokine-elicited intestinal epithelial responses during helminth infection.

Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D2 (PGD2) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced worm clearance and intestinal goblet cell hyperplasia following infection with the helminth Nippostrongylus brasiliensis. Small intestinal stem, goblet, and tuft cells expressed CRTH2. CRTH2-deficient small intestinal organoids showed enhanced budding and terminal differentiation to the goblet cell lineage. During helminth infection or in organoids, PGD2 and CRTH2 down-regulated intestinal epithelial Il13ra1 expression and reversed Type 2 cytokine-mediated suppression of epithelial cell proliferation and promotion of goblet cell accumulation. These data show that the PGD2-CRTH2 pathway negatively regulates the Type 2 cytokine-driven epithelial program, revealing a mechanism that can temper the highly inflammatory effects of the anti-helminth response.

Chromosomal-Level Genome Assembly of the Painted Sea Urchin Lytechinus pictus: A Genetically Enabled Model System for Cell Biology and Embryonic Development.

The painted urchin Lytechinus pictus is a sea urchin in the family Toxopneustidae and one of several sea urchin species that are routinely used as an experimental research organism. Recently, L. pictus has emerged as a tractable model system for establishing transgenic sea urchin lines due to its amenability to long term laboratory culture. We present the first published genome of L. pictus. This chromosomal-level assembly was generated using Illumina sequencing in conjunction with Oxford Nanopore Technologies long read sequencing and HiC chromatin conformation capture sequencing. The 998.9-Mb assembly exhibits high contiguity and has a scaffold length N50 of 46.0 Mb with 97% of the sequence assembled into 19 chromosomal-length scaffolds. These 19 scaffolds exhibit a high degree of synteny compared with the 19 chromosomes of a related species Lytechinus variegatus. Ab initio and transcript evidence gene modeling, combined with sequence homology, identified 28,631 gene models that capture 92% of BUSCO orthologs. This annotation strategy was validated by manual curation of gene models for the ABC transporter superfamily, which confirmed the completeness and accuracy of the annotations. Thus, this genome assembly, in conjunction with recent high contiguity assemblies of related species, positions L. pictus as an exceptional model system for comparative functional genomics and it will be a key resource for the developmental, toxicological, and ecological biology scientific communities.

Escherichiacoli-Specific CD4+ T Cells Have Public T-Cell Receptors and Low Interleukin 10 Production in Crohn's Disease.

BACKGROUND & AIMS: Crohn's disease (CD) likely represents decreased immune tolerance to intestinal bacterial antigens. Most CD patients have high titers of antibodies to intestinal commensal proteins, including the outer membrane porin C (OmpC) of Escherichia coli. METHODS: By using major histocompatibility complex II tetramers, we identified an HLA-DRB1∗15:01-restricted peptide epitope of OmpC recognized by CD4+ T cells in peripheral blood mononuclear cells from HLA-DRB1∗15:01+ healthy control (HC) and CD patients. RESULTS: The precursor frequency of these cells in CD correlated with anti-OmpC IgA titers, but did not differ from that of HCs. In both cohorts, they showed a CD161+, integrin α4ß7+ phenotype ex vivo by flow cytometry, distinct from the C-X-C Motif Chemokine Receptor 3 phenotype of autologous influenza hemagglutinin (Flu) peptide-specific T cells. The T-cell receptor α and ß chains of in vitro-expanded OmpC-specific T-cell clones often contained public amino acid sequences that were identical in cells from different patients. Expanded T-cell clones from CD subjects produced significantly less interleukin (IL)10 (P < .0001) than those from HCs, and a trend toward decreased production of the T helper 2 cell-associated IL4, IL5, and IL13 by CD clones also was seen. CONCLUSIONS: Both HCs and CD patients have detectable OmpC-specific T cells in circulation, with similar immunophenotypes and often identical T-cell-receptor sequences. However, expanded clones from patients with CD produce less of the immunoregulatory cytokine IL10, showing a selective defect in the regulatory function of intestinal microbial antigen-specific T cells in patients with CD.

Catastrophic High School and Collegiate Cheerleading Injuries in the United States: An Examination of the 2006-2007 Basket Toss Rule Change.

BACKGROUND:: Cheerleading is a specialized athletic activity that can lead to catastrophic injuries. Cheerleading rules are in place to maximize safety of participants. The purpose of this study was to describe catastrophic cheerleading injuries among high school and collegiate-level participants in the United States and to explore whether the 2006-2007 basket toss rule change was effective at reducing the number of catastrophic injuries. HYPOTHESIS:: The 2006-2007 basket toss rule change contributed to a reduction in the number of catastrophic injuries among high school and collegiate cheerleaders. STUDY DESIGN:: Case series. LEVEL OF EVIDENCE:: Level 4. METHODS:: Data on catastrophic cheerleading injuries were collected by the National Center for Catastrophic Sport Injury Research from July 2002 to June 2017. Information collected included cheerleader, event, and injury characteristics. The impact of the 2006-2007 rule change banning the basket toss on any hard surfaces was assessed by comparing injury rates and 95% CIs before and after the rule change. RESULTS:: There were 54 catastrophic cheerleading injuries, or 3.6 injuries per year. From July 2002 through June 2017, the injury rate was 2.12 per 1,000,000 cheerleaders (95% CI, 1.56-2.69). Most cheerleaders sustained serious injuries (n = 27; 50%) during practice (n = 37; 69%) to the head (n = 28; 52%) and cervical spine (n = 17; 32%). From July 2002 through June 2017, basket tosses were the stunt that accounted for the highest proportion of injuries (n = 19; 35%). The basket toss injury rate decreased from 1.55 to 0.40 per 1,000,000 cheerleaders among both high school and collegiate cheerleaders after the rule change. CONCLUSION:: Catastrophic injury rates in cheerleading decreased dramatically after the 2006-2007 rule change banning basket tosses from being performed on any hard surfaces. In particular, there was a nearly 4-fold reduction in the rate of catastrophic basket toss injuries.

High-dimensional immune phenotyping and transcriptional analyses reveal robust recovery of viable human immune and epithelial cells from frozen gastrointestinal tissue.

Simultaneous analyses of peripheral and mucosal immune compartments can yield insight into the pathogenesis of mucosal-associated diseases. Although methods to preserve peripheral immune cells are well established, studies involving mucosal immune cells have been hampered by lack of simple storage techniques. We provide a cryopreservation protocol allowing for storage of gastrointestinal (GI) tissue with preservation of viability and functionality of both immune and epithelial cells. These methods will facilitate translational studies allowing for batch analysis of mucosal tissue to investigate disease pathogenesis, biomarker discovery and treatment responsiveness.

Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype.

Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.

Identification of Candidate Biomarkers Associated with Response to Vedolizumab in Inflammatory Bowel Disease.

BACKGROUND/AIMS: Vedolizumab is an anti-α4ß7 monoclonal antibody approved for the treatment of inflammatory bowel disease (IBD). This exploratory study aimed to identify biomarkers associated with vedolizumab response. METHODS: Twenty-six IBD patients (15 with Crohn's, 11 with ulcerative or indeterminate colitis) initiating vedolizumab at a single center between 2014 and 2016 underwent sampling of serum and peripheral blood mononuclear cells (PBMCs) before and during vedolizumab therapy. Response was defined as steroid-free improvement in endoscopic score or Harvey-Bradshaw index/simple clinical colitis activity index (reduction greater than 3 or total less than 3). PBMCs were evaluated for immunophenotype and expression of α4ß7 integrin on lymphocytes before and during vedolizumab therapy. Serum vedolizumab levels and α4ß7 saturation were measured serially after induction. RESULTS: Fourteen out of 26 (54%) patients treated with vedolizumab responded to therapy. Pretreatment α4ß7 expression was higher in responders on multiple subsets of T, B, and NK cells, with terminal effector memory (p = .0009 for CD4 and .0043 for CD8) and NK cells (p = .0047) best discriminating between responders and nonresponders. During therapy, log10 serum vedolizumab levels at trough were higher in responders than nonresponders (p = .0007). Conversely, the percentage of effector memory T cells with free α4ß7 at trough was lower in responders than nonresponders (p < .0001). However, loss of α4ß7 saturation with vedolizumab was more sensitive to low serum vedolizumab in nonresponders. CONCLUSIONS: Pretreatment α4ß7 expression and α4ß7 receptor saturation during maintenance therapy were identified as candidate biomarkers for vedolizumab response.