scholarly journals DOP17 Identification of biomarkers and mechanistic insight for upadacitinib in ulcerative colitis: Analysis of serum inflammatory mediators in the phase 2b U-ACHIEVE study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S057-S058
Author(s):  
S Vermeire ◽  
H Guay ◽  
B Verstockt ◽  
J Fann ◽  
J Cheng ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dendritic Cell ◽  
Inflammatory Mediators ◽  
Immune Cell ◽  
Cell Activity ◽  
Type I ◽  
Serum Samples ◽  
Cell Responses ◽  
Immune Cell Migration ◽  
Migration Type

Abstract Background The U-ACHIEVE trial evaluated upadacitinib (UPA), an oral JAK1 selective inhibitor, in patients with moderately to severely active ulcerative colitis (UC). Patient-reported and endoscopic outcomes improved after UPA treatment. This analysis used pharmacodynamic profiling to link changes in serum biomarkers to changes in UC disease activity, and to assess the UPA mechanism of action in UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies were randomised to receive 7.5, 15, 30, or 45 mg UPA once daily or PBO for 8 weeks (weeks). Serum samples (baseline [BL], weeks 2, 4, and 8) were analysed by OLINK® inflammation panel (92 proteins) and by Singulex immunoassay for interleukin-1b (IL-1b), IL-17A, IL-17F, and IL-22. Protein-level changes were analysed by a mixed-effect model; BL protein level was adjusted as a covariate; treatment group, time point, and their interaction were included as fixed effects. Spearman rank-correlation coefficients were used to determine the relationship between changes of serum biomarker levels and improvements in adapted Mayo scores and endoscopic subscores. Multiplicity adjusted P values were calculated using 1000 runs of random permutations. Results Paired BL and week 8 serum samples were available from 114 patients (PBO, n = 17; UPA 7.5 mg, n = 21; UPA 15 mg, n = 21; UPA 30 mg, n = 29; UPA 45 mg, n = 26). UPA treatment reduced expression of pro-inflammatory mediators associated with immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity and increased expression of biomarkers associated with haematopoiesis, neuroprotection and mucosal repair in a dose-dependent manner. Improvements in adapted Mayo score, endoscopic subscore, and stool frequency correlated with increases in CX3CL1, DNER and FLt3L (p < 0.05 for all). Endoscopic improvements correlated with reductions in OSM, and improvements in fatigue correlated with increases in CCL25 and NT-3. There was a substantial overlap in biomarkers modulated by UPA in patients with UC and Crohn’s disease (Figure). Conclusion UPA modulated expression of serum pro-inflammatory mediators found in pathways associated with the pathogenesis of UC, including immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity, haematopoiesis, neuroprotection, and mucosal repair. Consistent correlations were observed between changes in biomarker expression and improvements in disease activity and symptoms of UC.

scholarly journals Clonal Type I Interferon–producing and Dendritic Cell Precursors Are Contained in Both Human Lymphoid and Myeloid Progenitor Populations

2004 ◽  
Vol 200 (11) ◽  
pp. 1519-1524 ◽  
Author(s):  
Laurie Chicha ◽  
David Jarrossay ◽  
Markus G. Manz
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Progenitor Cells ◽  
Type I Interferon ◽  
Cell Activity ◽  
Cell Development ◽  
Type I ◽  
Vitro Assay ◽  
Clonal Type

Because of different cytokine responsiveness, surface receptor, and transcription factor expression, human CD11c− natural type I interferon–producing cells (IPCs) and CD11c+ dendritic cells were thought to derive through lymphoid and myeloid hematopoietic developmental pathways, respectively. To directly test this hypothesis, we used an in vitro assay allowing simultaneous IPC, dendritic cell, and B cell development and we tested lymphoid and myeloid committed hematopoietic progenitor cells for their developmental capacity. Lymphoid and common myeloid and granulocyte/macrophage progenitors were capable of developing into both functional IPCs, expressing gene transcripts thought to be associated with lymphoid lineage development, and into dendritic cells. However, clonal progenitors for both populations were about fivefold more frequent within myeloid committed progenitor cells. Thus, in humans as in mice, natural IPC and dendritic cell development robustly segregates with myeloid differentiation. This would fit with natural interferon type I–producing cell and dendritic cell activity in innate immunity, the evolutionary older arm of the cellular immune system.

scholarly journals Sphingosine Analogue AAL-R Increases TLR7-Mediated Dendritic Cell Responses via p38 and Type I IFN Signaling Pathways

2012 ◽  
Vol 188 (10) ◽  
pp. 4759-4768 ◽  
Author(s):  
Young-Jin Seo ◽  
Curtis J. Pritzl ◽  
Madhuvanthi Vijayan ◽  
Celeste R. Blake ◽  
Mariah E. McClain ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Signaling Pathways ◽  
Type I ◽  
Type I Ifn ◽  
Cell Responses

scholarly journals A6 THE ROLE OF TUFT CELLS IN INTESTINAL HOMEOSTASIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 6-7
Author(s):  
A Zhang ◽  
Y Pang ◽  
S Menzies ◽  
L M Sly
Keyword(s):  
Disease Activity ◽  
Cell Activity ◽  
Sh2 Domain ◽  
Type I ◽  
Type Ii ◽  
Wild Type ◽  
Cell Responses ◽  
Tuft Cell ◽  
Tuft Cells

Abstract Background Intestinal epithelial cells may actively regulate homeostasis by recognizing and responding to extracellular signals. One of these cell types, tuft cells, has been proposed to have a role in secretion, absorption, and reception. However, their role in the intestine has not been fully characterized. We have found that tuft cells express the SH2 domain-containing inositol 5’-phosphatase (SHIP), which was formerly thought to be restricted to hematopoietic cells. SHIP negatively regulates PI3K-mediated cell growth, proliferation, and activation. Tuft cells secrete IL-25, which activates group 2 innate lymphoid cells (ILC2s), leading to type 2 immune responses. Tuft cells may contribute to inflammation in the intestine by increasing ILC2 numbers and/or activation, leading to type II inflammation. Aims My hypothesis is that SHIP inhibits tuft cell responses to innate immune stimuli by limiting PI3K activation. Moreover, SHIP deficiency will increase tuft cell responses to commensal microbes, causing ILC2-mediated type II inflammation. To investigate the role of SHIP in tuft cell responses in vivo, I will use a tuft cell-specific SHIP deficient mouse in the dextran sodium sulfate (DSS)-induced colitis model. Methods We created a mouse deficient in SHIP only in intestinal tuft cells (Fabpcre x SHIPfl/fl) to investigate the impact of SHIP deficiency in tuft cells on responses to luminal microbes. Tuft cell-specific SHIP deficient mice (8-week-old) and their wild type littermates were subjected to DSS-induced colitis for 7 days. Clinical disease activity was monitored daily and gross pathology, including total colon length, was examined at the experimental endpoint. The concentrations of pro-inflammatory type I and type II cytokines were assessed in colonic tissue homogenates via ELISA. Results During DSS-induced colitis, mice with SHIP deficient tuft cells had increased disease activity compared to their wild type littermates, particularly evident in their weight loss. Mice with SHIP deficient tuft cells also had significantly shorter colons than their wild type littermates. IL-25 concentrations (produced by tuft cells) were increased in full thickness colon homogenates from mice with SHIP deficient tuft cells. In contrast, pro-inflammatory cytokines IL-1β, IL-6, and TNF did not differ between genotypes. Thus, increased tuft cell activity due to SHIP deficiency correlated with increased disease severity during DSS-induced colitis. Conclusions SHIP deficiency in intestinal tuft cells leads to increased tuft cell activity and exacerbated colitis during DSS treatment. Tuft cells may contribute to inflammation via IL-25 production, leading to increased type II inflammation by ILC2s. In future studies, we will target IL-25 in this model to determine whether increased tuft cell IL-25 production plays a causal role in disease exacerbation. Funding Agencies NSERC

scholarly journals EXTH-04. INTRATHECAL (IT) DELIVERY OF TYPE I POLARIZED DENDRITIC CELL VACCINE (DC1) ERADICATES TUMOR GROWTH IN BREAST CANCER (BC) XENOGRAFT MODEL WITH BRAIN METASTASES (BM) AND LEPTOMENINGEAL DISEASE (LMD)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii87-ii87
Author(s):  
Vincent Law ◽  
Krithika Kodumudi ◽  
Colin Snyder ◽  
Brian Czerniecki ◽  
Peter Forsyth
Keyword(s):  
Dendritic Cell ◽  
Immune Cell ◽  
Tumor Regression ◽  
Pathologic Complete Response ◽  
Xenograft Model ◽  
Dendritic Cell Vaccine ◽  
Complete Response ◽  
Cell Vaccine ◽  
Leptomeningeal Disease ◽  
Type I

Abstract BACKGROUND Approx. 5% of BM will also develop LMD. Currently there is no effective treatment for BC-associated BM/LMD. As systemic therapies do not prevent the disease recurrence and eventual death, the better option would be direct-targeted approach. We have shown that there is a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune response in BC patients (pts). In a clinical setting, administration of class II HER2 peptide-pulsed Type I polarized dendritic cell vaccine (HER2-DC1) partially restored anti-HER2 Th1 immune responses with pathologic complete response in HER2+ BC patients. In this study, we examined the IT delivery of HER2/HER3- DC1 in BC-LMD model. METHODS Luciferase-labeled HER2+ TUBO BC cell line was injected into the cisterna magna of BALB/c mice to develop BM/LMD. We developed a technique, coined the “Top Hat” (TH) for mouse model that mimics the Ommaya reservoir in BC-pts. The TH essentially allows us to administer IT treatment directly into CSF. BC-BM/LMD bearing mice were given HER2- and Her3 peptide-pulsed Type I polarized DC1 through the TH. RESULTS AND DISCUSSION BM/LMD mice were randomized into following groups: 1) systemic Her2-DC1 2) IT Her2-DC1 3) IT Her2-/Her3-DC1. The median survival (MS) of control mice was 10 days and systemically treated mice was 19 days. IT Her2-DC1 animals did significantly better than both control and systemic treated groups (MS: 63 days; p< 0.0001) and overall survival (OS): 44%. Interestingly, mice given IT Her2-/Her3-DC1 had the best OS (78%). Surviving animals were eventually disease free. Mice that had complete tumor regression were immune to subsequent rechallenge with TUBO cells. Immune cell infiltration in the of CSF, spinal cord and tissues of experimental mice are currently ongoing. CONCLUSIONS Our preclinical data supports the clinical relevance of using intrathecal delivery of DC1 vaccine as a potential treatment for BM and LMD of BC-pts.

scholarly journals Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases

2018 ◽  
Vol 9 (1) ◽  
pp. 64-79 ◽  
Author(s):  
Gunjan Kak ◽  
Mohsin Raza ◽  
Brijendra K Tiwari
Keyword(s):  
Infectious Diseases ◽  
Antigen Processing ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Activity ◽  
Type I ◽  
Altered Expression ◽  
Ifn Γ

AbstractA key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers. It can exhibit its immunomodulatory effects by enhancing antigen processing and presentation, increasing leukocyte trafficking, inducing an anti-viral state, boosting the anti-microbial functions and affecting cellular proliferation and apoptosis. A complex interplay between immune cell activity and IFN-γ through coordinated integration of signals from other pathways involving cytokines and Pattern Recognition Receptors (PRRs) such as Interleukin (IL)-4, TNF-α, Lipopolysaccharide (LPS), Type-I Interferons (IFNS) etc. leads to initiation of a cascade of pro-inflammatory responses. Microarray data has unraveled numerous genes whose transcriptional regulation is influenced by IFN-γ. Consequently, IFN-γ stimulated cells display altered expression of many such target genes which mediate its downstream effector functions. The importance of IFN-γ is further reinforced by the fact that mice possessing disruptions in the IFN-γ gene or its receptor develop extreme susceptibility to infectious diseases and rapidly succumb to them. In this review, we attempt to elucidate the biological functions and physiological importance of this versatile cytokine. The functional implications of its biological activity in several infectious diseases and autoimmune pathologies are also discussed. As a counter strategy, many virulent pathogenic species have devised ways to thwart IFN-γ endowed immune-protection. Thus, IFN-γ mediated host-pathogen interactions are critical for our understanding of disease mechanisms and these aspects also manifest enormous therapeutic importance for the annulment of various infections and autoimmune conditions.

scholarly journals Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection

2014 ◽  
Vol 211 (5) ◽  
pp. 961-974 ◽  
Author(s):  
Shivani Srivastava ◽  
Meghan A. Koch ◽  
Marion Pepper ◽  
Daniel J. Campbell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Acute Infection ◽  
Cell Activity ◽  
T Cell Responses ◽  
Type I Interferons ◽  
Type I ◽  
Cell Responses ◽  
Lcmv Infection

Regulatory T (T reg) cells play an essential role in preventing autoimmunity but can also impair clearance of foreign pathogens. Paradoxically, signals known to promote T reg cell function are abundant during infection and could inappropriately enhance T reg cell activity. How T reg cell function is restrained during infection to allow the generation of effective antiviral responses remains largely unclear. We demonstrate that the potent antiviral type I interferons (IFNs) directly inhibit co-stimulation–dependent T reg cell activation and proliferation, both in vitro and in vivo during acute infection with lymphocytic choriomeningitis virus (LCMV). Loss of the type I IFN receptor specifically in T reg cells results in functional impairment of virus-specific CD8+ and CD4+ T cells and inefficient viral clearance. Together, these data demonstrate that inhibition of T reg cells by IFNs is necessary for the generation of optimal antiviral T cell responses during acute LCMV infection.

S1PR4 is required for plasmacytoid dendritic cell differentiation

2015 ◽  
Vol 396 (6-7) ◽  
pp. 775-782 ◽  
Author(s):  
Christina Dillmann ◽  
Javier Mora ◽  
Catherine Olesch ◽  
Bernhard Brüne ◽  
Andreas Weigert
Keyword(s):  
Dendritic Cell ◽  
Cell Biology ◽  
Cell Function ◽  
Immune Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Type I ◽  
Hematopoietic Stem ◽  
Dendritic Cell Differentiation ◽  
Sphingosine 1 Phosphate

Abstract The sphingolipid sphingosine-1-phosphate (S1P) has various functions in immune cell biology, regulating survival, proliferation, and, most prominently, migration. S1P couples to five G protein-coupled receptors (S1PR1–5) to transduce its effects on immune cell function. Expression of S1PR4 is restricted to immune cells. However, its impact on immune cell biology is largely elusive. In the current study, we intended to answer the question of whether S1P might affect plasmacytoid dendritic cell (pDC) migration, which dominantly express S1PR4. pDC are highly specialized cells producing large amounts of type I interferon in response to TLR7/9 ligands after viral infection or during autoimmunity. Surprisingly, we noticed a reduced abundance of pDC, particularly CD4- pDC, in all organs of S1PR4-deficient vs. wildtype mice. This effect was not caused by altered migration of mature pDC, but rather a reduced potential of pDC progenitors, especially common DC progenitors, to differentiate into pDCs. In vitro studies suggested that reduced S1PR4-deficient pDC progenitor differentiation into mature pDC might be explained by both migration and differentiation of pDC progenitors in the bone marrow. As S1PR4 also affected the differentiation of CD34+ human hematopoietic stem cells into pDC, interfering with S1PR4 might be useful to reduce pDC numbers during autoimmunity.

Altered myeloid and lymphoid immune cell responses following repeated social defeat stress

2015 ◽  
Vol 48 (06) ◽  
Author(s):  
O Ambree ◽  
C Ruland ◽  
P Zwanzger ◽  
V Arolt ◽  
J Alferink
Keyword(s):  
Immune Cell ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Cell Responses
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