scholarly journals Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn’s disease and regulate Th1/Th17 cell responses

2019 ◽  
Vol 32 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Jose E Aguirre ◽  
Ellen J Beswick ◽  
Carl Grim ◽  
Gabriela Uribe ◽  
Marissa Tafoya ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Matrix Metalloproteinases ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Surface Membrane ◽  
Cell Activity ◽  
Th1 Cell ◽  
Mmp Inhibitors ◽  
Membrane Bound

Abstract Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn’s disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.

scholarly journals P014 Identification of Crohn’s disease immunopathotypes

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S137-S137
Author(s):  
H M Baer ◽  
E MacDonald ◽  
A Ferguson ◽  
A M Scott ◽  
M I Khan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Local Immune Response ◽  
Cross Sectional ◽  
Treatment Responses ◽  
Colonic Biopsies

Abstract Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with globally increasing incidence. Patients with CD suffer from a loss of tolerance towards their commensal microbiota causing an aberrant immune response, occurring in a protracted relapse and remission cycle. Although a variety of frontline therapies is currently available, including targeted therapies such as biologic drugs, 30–40% of CD patients still require surgery to manage the disease. At present, the immunobiology of CD is not fully understood. However, differences in immune responses between patients might play an important role in diverse treatment responses. The aim of this study was to identify differences in peripheral and local immune responses of CD to understand differences in disease behaviour and treatment outcome. Methods Peripheral blood mononuclear cells and plasma were isolated from whole blood of a cross-sectional CD patient cohort (nCD = 12) and normal controls (NC, nNC = 28). Flow cytometry analysis and multiplex assays were used to quantify immune cell populations and cytokine levels, respectively. The local immune response was analysed by bulk RNA sequencing of mucosal colonic biopsies either from inflamed CD or normal tissue. Gene signatures were then followed up by validation in publicly deposited gene expression datasets (nCD = 36, nNC = 24), and by measurement of specific proteins using our archived samples. Results Peripheral immunophenotyping of the initial cross-sectional study displayed three different types of CD patients, characterised by either a decrease in leukocyte populations, an increase of cytokines, or a change in both. Analysis of the RNAseq data derived from colonic biopsies revealed four distinct clusters in genes associated with the immune response in CD patients. Further pathway analysis showed one cluster with an enriched B cell signature and another cluster with an elevated macrophage and neutrophil response. We utilised publicly available gene expression datasets to validate these signatures in a larger cohort and identified a selection of patients with an up-regulated pro-inflammatory macrophage response. Using correlation analysis, we suggest an immunopathotype with increased macrophage activation which is potentially associated with a more severe form of the disease. Conclusion We have identified distinct immunopathotypes in both the peripheral and local immune response of CD patients. Further investigation will correlate these distinct immune responses in CD with clinical parameters, to understand associations between diverse treatment responses and disease behaviours.

scholarly journals Hypogammaglobulinemia Due to Abnormal Suppressor T-Cell Activity in Crohn's Disease

1984 ◽  
Vol 86 (3) ◽  
pp. 569-576 ◽  
Author(s):  
Charles O. Elson ◽  
Stephen P. James ◽  
Alan S. Graeff ◽  
Robert A. Berendson ◽  
Warren Strober
Keyword(s):  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Cell Activity ◽  
Suppressor T Cell

scholarly journals STAT3 Genotypic Variant rs744166 and Increased Tyrosine Phosphorylation of STAT3 in IL-23 Responsive Innate Lymphoid Cells during Pathogenesis of Crohn’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Ying Tang ◽  
Sanda A. Tan ◽  
Atif Iqbal ◽  
Jian Li ◽  
Sarah C. Glover
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Tyrosine Phosphorylation ◽  
Innate Lymphoid Cells ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Dependent Manner ◽  
Regulatory Pathways ◽  
Innate Effector

Crohn’s disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele “A” with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 “A” risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse.

scholarly journals Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn’s disease

2002 ◽  
Vol 61 (1) ◽  
pp. 123-130 ◽  
Author(s):  
Miranda C. E. Lomer ◽  
Richard P. H. Thompson ◽  
Jonathan J. Powell
Keyword(s):  
Crohn’S Disease ◽  
Gastrointestinal Tract ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Ultrafine Particles ◽  
Activity Index ◽  
Food Additives ◽  
Disease Activity Index ◽  
Mucosal Immune Response ◽  
Double Blind

Crohn’s disease is a modern Western disease characterised by transmural inflammation of the gastrointestinal tract. It is of unknown aetiology, but evidence suggests that it results from a combination of genetic predisposition and environmental factors. Bacterial-sized microparticles (0·1–1·0 µm) are potent adjuvants in model antigen-mediated immune responses and are increasingly associated with disease. Microparticles of TiO2 and aluminosilicate accumulate in macrophages of human gut-associated lymphoid tissue where the earliest signs of lesions in Crohn’s disease are observed. Dietary microparticles are of endogenous or exogenous origin. Endogenous microparticles dominate and are calcium phosphate (most probably hydroxyapatite), which precipitates in the lumen of the mid-distal gastrointestinal tract due to secretion of Ca and phosphate in the succus entericus. Exogenous dietary microparticles are contaminants (soil and/or dust) and food additives. TiO2, for example, is a food colourant, and aluminosilicates are anti-caking agents, although some aluminosilicates occur as natural contaminants. Food additives alone account for ingestion of approximately 1012 particles/person per d. Possible mechanisms for the role of exogenous and endogenous dietary microparticles in promoting toleragenic or immune responses of gastrointestinal mucosal phagocytosis are discussed. In a double-blind randomised pilot study we have shown that a diet low in Ca and exogenous microparticles appears to alleviate the symptoms of ileal Crohn’s disease, with a significant (P = 0·002) improvement in the Crohn’s disease activity index. A multi-centre trial and further mechanistic studies at the cellular level are underway.

scholarly journals 578. INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell Activity Against Global SARS-CoV-2 Variants

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S390-S391
Author(s):  
Viviane M Andrade ◽  
Aaron Christensen-Quick ◽  
Joseph Agnes ◽  
Jared Tur ◽  
Charles C Reed ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Dna Vaccine ◽  
Stock Options ◽  
Neutralizing Antibodies ◽  
Cell Activity ◽  
Cellular Responses ◽  
Neutralization Assay ◽  
Material Support ◽  
Fold Reduction

Abstract Background Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with increased transmissibility, disease severity, and resistance to neutralization by current vaccines under emergency use authorization (EUA). Here we assessed cross-immune responses of INO-4800 vaccinated subjects against SARS-CoV-2 VOCs. Methods We used a SARS-CoV-2 IgG ELISA and a pseudo neutralization assay to assess humoral responses, and an IFNγ ELISpot to measure cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. Results IgG binding titers were not impacted between wild-type (WT) and B.1.1.7 or B.1.351 variants. An average 1.9-fold reduction was observed for the P.1 variant in subjects tested at week 8 after receiving two doses of INO-4800 (Figure 1a). We performed a SARS-CoV-2 pseudovirus neutralization assay using sera collected from 13 subjects two weeks after administration of a third dose of either 0.5 mg, 1 mg, or 2 mg of INO-4800. Neutralization was detected against WT and the emerging variants in all samples tested. The mean ID50 titers for the WT, B.1.1.7, B.1.351 and P.1. were 643 (range: 70-729), 295 (range: 46-886), 105 (range: 25-309), and 664 (range: 25-2087), respectively. Compared to WT, there was a 2.1 and 6.9-fold reduction for B.1.1.7 and B.1.351, respectively, while there was no difference between WT and the P.1 variant (Figure 1b). Next, we compared cellular immune responses to WT and SARS-CoV-2 Spike variants elicited by INO-4800 vaccination. We observed similar cellular responses to WT (median = 82.2 IQR = 58.9-205.3), B.1.1.7 (79.4, IQR = 38.9- 179.7), B.1.351 (80, IQR = 40.0-208.6) and P.1 (78.3, IQR = 53.1-177.8) Spike peptides (Figure 2). Conclusion INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested. Disclosures Viviane M. Andrade, PhD, Inovio Pharmaceuticals Inc. (Employee) Aaron Christensen-Quick, PhD, Inovio Pharmaceuticals, Inc (Employee) Joseph Agnes, PhD, Inovio (Employee, Shareholder) Jared Tur, PhD, Inovio (Employee) Charles C. Reed, PhD, Inovio Pharmaceuticals (Employee, Shareholder) Richa Kalia, MS, Inovio Pharmaceuticals (Employee, Other Financial or Material Support, I have stock options with Inovio Pharmaceuticals as an employee.) Idania Marrero, MD, PhD, Inovio Pharmaceuticals (Employee, Shareholder) Dustin Elwood, PhD, Inovio Pharmaceuticals (Employee) Katherine Schultheis, MSc, Inovio Pharmaceuticals (Employee) Emma Reuschel, PhD, Inovio Pharmaceuticals (Employee) Trevor McMullan, MSc, Inovio (Shareholder) Patrick Pezzoli, BS, Inovio (Employee) Kimberly A. Kraynyak, PhD, Inovio Pharmaceuticals (Employee, Other Financial or Material Support, Stock options) Albert Sylvester, MS, Inovio (Employee, Shareholder) Mammen P. Mammen Jr., MD, Inovio Pharmaceuticals (Employee) J Joseph Kim, PhD, Inovio (Employee) David Weiner, PhD, Inovio (Board Member, Grant/Research Support, Shareholder, I serve on the SAB in addition to the above activities) Trevor R. F. Smith, PhD, Inovio (Employee, Shareholder) Stephanie Ramos, PhD, Inovio Pharmaceuticals (Employee) Laurent Humeau, PhD, Inovio Pharmaceuticals (Employee) Jean Boyer, PhD, Inovio (Employee) Kate Broderick, PhD, Inovio (Employee)

scholarly journals High Immunogenicity to Influenza Vaccination in Crohn’s Disease Patients Treated with Ustekinumab

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 455
Author(s):  
Laura Doornekamp ◽  
Rogier L. Goetgebuer ◽  
Katharina S. Schmitz ◽  
Marco Goeijenbier ◽  
C. Janneke van der Woude ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Influenza Vaccination ◽  
Seasonal Influenza ◽  
T Cell Responses ◽  
Healthy Controls ◽  
Post Vaccination ◽  
Cell Responses

Influenza vaccination can be less effective in patients treated with immunosuppressive therapy. However, little is known about the effects of ustekinumab; an anti-IL-12/23 agent used to treat Crohn’s disease (CD), on vaccination response. In this prospective study, we assessed immune responses to seasonal influenza vaccination in CD patients treated with ustekinumab compared to CD patients treated with anti-TNFα therapy (adalimumab) and healthy controls. Humoral responses were assessed with hemagglutinin inhibition (HI) assays. Influenza-specific total CD3+, CD3+CD4+, and CD3+CD8+ T-cell responses were measured with flow cytometry. Fifteen patients treated with ustekinumab; 12 with adalimumab and 20 healthy controls were vaccinated for seasonal influenza in September 2018. Seroprotection rates against all vaccine strains in the ustekinumab group were high and comparable to healthy controls. Seroconversion rates were comparable, and for A/H3N2 highest in the ustekinumab group. HI titers were significantly higher in the ustekinumab group and healthy controls than in the adalimumab group for the B/Victoria strain. Post-vaccination T-cell responses in the ustekinumab group were similar to healthy controls. One-month post-vaccination proliferation of CD3+CD8+ T-cells was highest in the ustekinumab group. In conclusion, ustekinumab does not impair immune responses to inactivated influenza vaccination. Therefore, CD patients treated with ustekinumab can be effectively vaccinated for seasonal influenza.

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