scholarly journals Evaluation of Th9 lymphocytes in peripheral blood of rheumatoid arthritis patients and correlation with anti-tumor necrosis factor therapy: results from an in vitro pivotal study

Reumatismo ◽  
2016 ◽  
Vol 68 (2) ◽  
pp. 83 ◽  
Author(s):  
R. Talotta ◽  
A. Berzi ◽  
F. Atzeni ◽  
D. Dell'Acqua ◽  
P. Sarzi Puttini ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Peripheral Blood ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Healthy Controls ◽  
T Helper ◽  
Th9 Cells ◽  
Necrosis Factor

The aim of this study was to determine the prevalence of T helper 9 (Th9) lymphocytes in rheumatoid arthritis (RA) patients and to identify a possible association between the percentage of Th9 and the discontinuation of a biological treatment with an anti-tumor necrosis factor (TNF) (infliximab). We collected peripheral blood mononuclear cells (PBMCs) from 55 consecutive RA outpatients and 10 healthy controls. Among RA patients, 15 were not receiving any immunosuppressive drug, 20 were successfully treated with infliximab and 20 discontinued infliximab because of adverse events or inefficacy and were treated with other biological agents. PBMCs were cultured with/without infliximab 50 mg/L for 18 h, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were identified as interferon gamma, interleukin (IL)4-, IL17-, IL9-secreting cluster of differentiation 4 (CD4)+ T cells. Cytometric analysis revealed no significant decrease in the percentage of Th9 cells after infliximab exposure in any of the groups, although it was lower in healthy controls than RA patients either before and after the infliximab stimulation assay. Th9 cells are IL-9-secreting T helper lymphocytes whose role in RA is still poorly known. IL-9 levels are increased in RA patients, in whom this cytokine plays a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects; however our experiment <em>in vitro</em> does not demonstrate an association between Th9 lymphocytes and the response to infliximab. Further studies are required to evaluate the real involvement of Th9 population in the immunogenicity of anti-TNF agents.

scholarly journals Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency--possible immunologic and clinical consequences

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 674-681 ◽  
Author(s):  
P Aukrust ◽  
E Lien ◽  
AK Kristoffersen ◽  
F Muller ◽  
CJ Haug ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Common Variable Immunodeficiency ◽  
Peripheral Blood ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Tnf Alpha ◽  
Healthy Controls ◽  
Necrosis Factor ◽  
Common Variable

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVIHyper) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNF alpha and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNF alpha and both types of sTNFRs, with the highest levels in the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVIHyper patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVIHyper patients also had significantly higher TNF alpha:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVIHyper subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.

scholarly journals AB0107 INVESTIGATION OF THE EFFECTS OF KYNURENIC ACID ANALOGS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1352.1-1353
Author(s):  
B. Varga ◽  
A. Balog ◽  
F. Fülöp ◽  
L. Vécsei ◽  
Y. Mándi
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Kynurenic Acid ◽  
Mononuclear Cells ◽  
Activity Score ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Necrosis Factor

Background:The investigation of anti-inflammatory and immunosuppressive functions of kynurenic acid (KYNA) is now in focus. Previously, we demonstrated the opposite effects of KYNA and different KYNA analogs on tumor necrosis factor-α (TNF-α) production and tumor necrosis factor-stimulated gene-6 (TSG-6) expression in U-937 monocytic cells. The potential effect of KYNA analogs on further immune mediators including alarmins (S100A12=EN-RAGE and S100A8/9=calprotectin), and on human neutrofil peptide 1-3(α-defensin) production has not been investigated.Objectives:Therefore, in the present study, we compared the effects of newly synthesized KYNA analog on the TNF-α, alarmins and α-defensin production, correlation with the effects on the TSG-6 expression in rheumatoid arthritis (RA).Methods:93 RA patients were involved and divided subgroups based on DAS28 activity score. Peripheral blood mononuclear cells (PBMC) was isolated from RA patients and healthy controls. As cytokine inducers heat inactivatedStaphylococcus aureus(SA1) were used. In parallel in vitro experiments, the SA1 induced PBMCs were pretreated with a newly synthesized KYNA analog (compound SZR-72 was synthesized by direct amidation of KYNA). The concentrations of the above mentioned inflammatory mediators in the supernatants were quantified by using ELISA kits and the TSG-6 expression was also determined by RTqPCR method.Results:The SA1 induced TNF-α, EN-RAGE, calprotectin and α-defensin production was significantly higher in RA patients’ group than in healthy controls. KYNA analog attenuated the SA1 induced TNF-α, EN-RAGE, calprotectin and α-defensin production, and increased TSG-6 production and TSG-6 mRNA expression in PBMC cells from RA patients. The SA1 induced TNF-α and TSG-6 production correlated with the DAS28 activity score. The TNF-α inhibitory effect of the KYNA analog correlated inversely with the TSG-6 stimulatory effect in all subgroups of RA patients based on DAS28 activity score.Conclusion:TSG-6 expression could participate in the suppression of inflammatory cytokines, such as TNF-α, EN-RAGE, calprotectin and α-defensin. We suppose that the elevation of the TSG-6 expression by KYNA and especially by new KYNA analogs might be one of the mechanisms that are responsible for their suppressive effect on TNF-α production as a feedback mechanism in RA. KYNA and KYNA analogs have an important role in influencing TSG-6 expression, and there is a possible benefit with potential therapeutic consequence of targeting TSG-6 expression by kynurenines in inflammatory conditions in RA.References:[1]Mándi Y, Endrész V, Mosolygó T, Burián K, Lantos I, Fülöp F, Szatmári I, Lőrinczi B, Balog A, Vécsei L, The Opposite Effects of Kynurenic Acid and Different Kynurenic Acid Analogs on Tumor Necrosis Factor-a (TNF-a) Production and Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6) Expression. Frontiers in Immunology. doi: 10.3389/fimmu.2019.01406Acknowledgments:This work was supported by GINOP 2.3.2-2015-16-00034Disclosure of Interests:None declared

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