Serum Levels of Vasoactive Intestinal Peptide as a Prognostic Marker in Early Arthritis

Martı́nez, Carmen; Ortiz, Ana M.; Juarranz, Yasmina; Lamana, Amalia; Seoane, Iria V.; Leceta, Javier; García‐Vicuña, Rosario; Gomariz, Rosa P.; González‐Álvaro, Isidoro

doi:10.1371/journal.pone.0085248

Cited by 36 publications

(51 citation statements)

References 31 publications

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“…In a recent elegant study, Sun et al described the beneficial role of VIP in UC patients. In agreement with data reported in several rheumatic diseases [245,275,276], they found that serum VIP levels are lower in UC patients than in healthy controls. The study provided evidence showing that VIP serum levels are lower in IgE + UC patients than that in IgE¯UC patients [268].…”

Section: Inflammatory Bowel Diseasesupporting

confidence: 91%

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

Martı́nez

Juarranz

Gutiérrez‐Cañas

et al. 2019

IJMS

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The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP’s discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

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Section: Inflammatory Bowel Diseasesupporting

confidence: 91%

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

Martı́nez

Juarranz

Gutiérrez‐Cañas

et al. 2019

IJMS

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“…The effect of VIP has been studied extensively in the immune system, and its function on innate and adaptive immunity has been demonstrated clearly, having a beneficial effect on the development of several autoimmune disorders in animal models and in patients with RA [19,20,[27][28][29][30][31][32]49]. Indeed, eRA patients who are unable to up-regulate VIP, present a worse clinical course despite receiving more intense treatment [33]. Its effect on Th1/Th2 balance has been examined in in vivo and in vitro studies.…”

Section: Discussionmentioning

confidence: 99%

“…In human RA, VIP is present in the microenvironment of the joints, and its therapeutic effects have been supported by several studies [20,[29][30][31][32]. Circulating VIP levels have been described as a prognostic biologic marker, predicting the evolution of eRA patients [33]. Moreover, recently, it has been described that the pattern expression of the VPAC receptors is altered in Th cells from eRA patients and that VIP can modulate their pathogenic profile [34].…”

Section: Introductionmentioning

confidence: 96%

Th17 polarization of memory Th cells in early arthritis: the vasoactive intestinal peptide effect

Jimeno

Leceta

Garín

et al. 2015

Journal of Leukocyte Biology

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Several studies in humans indicate the implication of Th17 cells in RA. Therapies targeting their pathogenicity, as well as their plasticity to the Th17/1 phenotype, could ameliorate the progression of the pathology. The neuroendocrine environment has a major impact on the differentiation of lymphoid cells. VIP is present in the microenvironment of the joint, and its known therapeutic effects are supported by several studies on RA. We examine the ability of VIP to modulate the differentiation of Th17 cells. Peripheral blood CD4(+)CD45RO(+) T cells from HD and eRA patients were expanded under Th17-polarizing conditions in the presence of TGF-β. After 7 days, the higher IL-17A, IL-21, and IL-9 levels and lower IL-22 levels indicate the nonpathogenic profile for Th17 cells in HD. In contrast, Th17 cells from eRA patients produced significantly more IL-22 and IFN-γ, and these cells show a more Th17/1 profile, indicating a pathogenic phenotype. Interestingly, when VIP was present in the Th17 conditioned medium, increased levels of IL-10 and IL-9 were detected in HD and eRA patients. VIP also reduced the levels of IL-22 in eRA patients. These data suggest that VIP reduces the pathogenic profile of the Th17-polarized cells. This effect was accompanied by an increased in the Treg/Th17 profile, as shown by the increase levels of Foxp3. In conclusion, this report addresses a novel and interesting question on the effect of VIP on human Th17 cells and adds clinical relevance by analyzing, in parallel, HD and eRA patients.

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“…VIP is one of the best-studied neuropeptides with anti-inflammatory and immunomodulatory actions in normal and pathological conditions (1,2,3). There are evidences that VIP may have therapeutic effects for human Rheumatoid arthritis and might be used as a prognostic marker for this disease (3,4). However, there are no deepen studies related to the expression pattern, cellular location, signalling pathways and functionality of its receptors (VPAC 1 and VPAC 2 ) during the activation of Th cells.…”

mentioning

confidence: 99%

“…Recently, using deep TCR profiling, new data supporting potential role of CD8+ T cells in AS have been published by our group and others [2,3]. Despite heterogeneous phenotype 24% of patients from combined cohort of AS and PsA fulfill both CASPAR and modified new-york criteria [4]. Also there is known tendency for axial disease in HLA-B*27+ PsA patients Objectives: Here we for the first time applied deep TCR profiling to study T cell repertoire of inflamed joints of patients with PsA, to characterise the similarity in clonal composition between patients in presence and absence of HLA-B*27…”

mentioning

confidence: 99%

Sat0031 vitamin B3 (Nam) Suppresses T Cell Activation in and Production of Pro-Inflammatory Cytokines in Vitro in a Dose Dependent Manner Indicating Therapeutic Potential for the Treatment of Jia

Nijhuis

Wetering

Houtzager

et al. 2019

Saturday, 15 June 2019

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Background:Impaired immunological tolerance in Juvenile Idiopathic Arthritis (JIA) is the result of a disturbed balance between regulatory T-cells (Tregs) and effector T-cells (Teffs). Restoring this balance by either enhancing the suppressive function of Tregs or inhibiting activity of pro-inflammatory Teffs seems a promising therapeutic strategy. We have previously demonstrated that high concentrations of Vitamin B3 (VitB3), also known as nicotinamide (NAM), lead to an increase in FOXP3 positive cells in vitro, via suppression of the deacetylase SIRT1. Because the transcription factor FOXP3 is essential for Treg function, this approach could promote immunological tolerance. We now aim to translate these laboratory findings into clinical practice and envision a role for VitB3 as a novel therapeutic strategy for patients with JIA. However, while VitB3 has promising effects on Tregs, the effect of VitB3 on Teff cells, the other side of the scale, is still unexplored.Objectives:To investigate the effect of VitB3/SIRT1 inhibition on proliferation, activation, cytokine production and TCR signaling of Teff cells.Methods:T-cells were isolated from the blood of healthy controls and JIA patients, as well as from the synovial fluid from JIA patients. Cells were stimulated with aCD3/aCD28 and cultured in the presence of increasing concentrations of VitB3 (0-9mM) for 1-4 days. Proliferation and expression of activation makers in primary T cells were determined using flow cytometry. Cytokine production was determined by qPCR, Luminex and flow cytometry. ERK phosphorylation was measured by flow cytometry and Western blot. ERK phosphorylation and GFP expression were also determined by flow cytometry using a murine NFAT-GFP reporter celline.Results:In vitro VitB3 treatment of JIA patient CD4+ Teff-cells significantly decreased the production of the pro-inflammatory cytokines IL-2 and IFNy measured both on mRNA and protein level. Correspondingly, surface activation markers were downregulated after VitB3 incubation, and ERK phosphorylation was decreased. Furthermore, proliferation of both CD4+ and CD8+ T-cells was inhibited with VitB3 treatment in a dose dependent manner. Murine reporter cells showed similar results. Experimental outcomes were verified using another SIRT1 inhibitor; EX-527.Conclusion:In addition to the previously demonstrated increase of Treg numbers and functioning, this data demonstrates that VitB3 treatment also inhibits proliferation and activation of Teff cells in vitro. VitB3 treatment could therefore modulate the immunological balance by both increasing tolerance and suppressing immune activation. We envision that VitB3 treatment as an adjuvant therapy has the potential to benefit JIA patients and potentially patients with other autoimmune diseases. To assess the clinical relevance of these findings, we are currently in the preparation of a phase III clinical trial.Disclosure of Interests:None declared

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Serum Levels of Vasoactive Intestinal Peptide as a Prognostic Marker in Early Arthritis

Cited by 36 publications

References 31 publications

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

Th17 polarization of memory Th cells in early arthritis: the vasoactive intestinal peptide effect

Sat0031 vitamin B3 (Nam) Suppresses T Cell Activation in and Production of Pro-Inflammatory Cytokines in Vitro in a Dose Dependent Manner Indicating Therapeutic Potential for the Treatment of Jia

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