9 research outputs found

    HuMoSC, une nouvelle thérapie pour le traitement des maladies dysimmunitaires et fibrosantes

    No full text
    Our team has developed an experimental method to generate immunosuppressive cells of monocyte origin called Human Monocyte-derived Suppressor Cells (HuMoSC). Although their immunosuppressive properties have already been shown, no study had yet evaluated their interest in tissue remodeling.The objective of this thesis was to evaluate the therapeutic potential of HuMoSCs and their supernatant for the treatment of tissue remodeling. On the other hand, we sought to identify the mechanisms of action involved in the functions of the supernatant of HuMoSC. The effect of HuMoSCs was first evaluated in giant cell arteritis using an ex vivo temporal artery culture model, and then in an in vitro and in vivo fibrosis model, similar to that described in Systemic Scleroderma.Our results showed that HuMoSC supernatant decreased the expression of matrix proteins and pro-fibrosing factors as well as cell proliferation.In conclusion, this thesis work has highlighted the anti-remodeling properties of HuMoSC supernatant thus representing a new hope in the treatment of fibrosing diseases.Notre Ă©quipe a dĂ©veloppĂ© une mĂ©thode expĂ©rimentale pour gĂ©nĂ©rer des cellules immunosuppressives d’origine monocytaire baptisĂ©es les Human Monocyte-derived Suppressor Cells (HuMoSC). Si leurs propriĂ©tĂ©s immunosuppressives ont dĂ©jĂ  Ă©tĂ© montrĂ©es, aucune Ă©tude n’avait encore Ă©valuĂ© leurs intĂ©rĂȘts sur le remodelage tissulaire.L'objectif de cette thĂšse Ă©tait d’une part, d'Ă©valuer le potentiel thĂ©rapeutique des HuMoSC et de leur surnageant pour le traitement du remodelage tissulaire. D’autre part, nous avons cherchĂ© Ă  identifier les mĂ©canismes d’action impliquĂ©s dans les fonctions du surnageant. L’effet des HuMoSC a d’abord Ă©tĂ© Ă©valuĂ© dans l'artĂ©rite Ă  cellules gĂ©antes en utilisant un modĂšle de culture d’artĂšres temporales ex vivo, puis dans un modĂšle de fibrose in vitro et in vivo, similaire Ă  celle dĂ©crite dans la SclĂ©rodermie SystĂ©mique.Nos rĂ©sultats ont montrĂ© que le surnageant de HuMoSC diminuait l’expression des protĂ©ines matricielles et des facteurs pro-fibrosants ainsi que la prolifĂ©ration cellulaire.En conclusion, ce travail de thĂšse a mis en avant les propriĂ©tĂ©s anti-remodelage du surnageant de HuMoSC, reprĂ©sentant ainsi un nouvel espoir dans le traitement des maladies fibrosantes

    HuMoSC, a new therapy for the treatment of auto-immune diseases and fibrosis

    No full text
    Notre Ă©quipe a dĂ©veloppĂ© une mĂ©thode expĂ©rimentale pour gĂ©nĂ©rer des cellules immunosuppressives d’origine monocytaire baptisĂ©es les Human Monocyte-derived Suppressor Cells (HuMoSC). Si leurs propriĂ©tĂ©s immunosuppressives ont dĂ©jĂ  Ă©tĂ© montrĂ©es, aucune Ă©tude n’avait encore Ă©valuĂ© leurs intĂ©rĂȘts sur le remodelage tissulaire.L'objectif de cette thĂšse Ă©tait d’une part, d'Ă©valuer le potentiel thĂ©rapeutique des HuMoSC et de leur surnageant pour le traitement du remodelage tissulaire. D’autre part, nous avons cherchĂ© Ă  identifier les mĂ©canismes d’action impliquĂ©s dans les fonctions du surnageant. L’effet des HuMoSC a d’abord Ă©tĂ© Ă©valuĂ© dans l'artĂ©rite Ă  cellules gĂ©antes en utilisant un modĂšle de culture d’artĂšres temporales ex vivo, puis dans un modĂšle de fibrose in vitro et in vivo, similaire Ă  celle dĂ©crite dans la SclĂ©rodermie SystĂ©mique.Nos rĂ©sultats ont montrĂ© que le surnageant de HuMoSC diminuait l’expression des protĂ©ines matricielles et des facteurs pro-fibrosants ainsi que la prolifĂ©ration cellulaire.En conclusion, ce travail de thĂšse a mis en avant les propriĂ©tĂ©s anti-remodelage du surnageant de HuMoSC, reprĂ©sentant ainsi un nouvel espoir dans le traitement des maladies fibrosantes.Our team has developed an experimental method to generate immunosuppressive cells of monocyte origin called Human Monocyte-derived Suppressor Cells (HuMoSC). Although their immunosuppressive properties have already been shown, no study had yet evaluated their interest in tissue remodeling.The objective of this thesis was to evaluate the therapeutic potential of HuMoSCs and their supernatant for the treatment of tissue remodeling. On the other hand, we sought to identify the mechanisms of action involved in the functions of the supernatant of HuMoSC. The effect of HuMoSCs was first evaluated in giant cell arteritis using an ex vivo temporal artery culture model, and then in an in vitro and in vivo fibrosis model, similar to that described in Systemic Scleroderma.Our results showed that HuMoSC supernatant decreased the expression of matrix proteins and pro-fibrosing factors as well as cell proliferation.In conclusion, this thesis work has highlighted the anti-remodeling properties of HuMoSC supernatant thus representing a new hope in the treatment of fibrosing diseases

    New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

    No full text
    The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by an unknown trigger. Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis. In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells

    Alteration of microbiota antibody‐mediated immune selection contributes to dysbiosis in inflammatory bowel diseases

    Get PDF
    International audienceHuman secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse-transcytosis, the apical-to-basal transport of IgA2 immune complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan-glycan interaction. Here, we asked whether IgA1 and IgA2-microbiota interactions might be involved in dysbiosis induction during inflammatory bowel diseases. Using stool HPLC-purified IgA, we show that reverse-transcytosis is abrogated in ulcerative colitis (UC) while it is extended to IgA1 in Crohn's disease (CD). 16S RNA sequencing of IgA-bound microbiota in CD and UC showed distinct IgA1- and IgA2-associated microbiota; the IgA1+ fraction of CD microbiota was notably enriched in beneficial commensals. These features were associated with increased IgA anti-glycan reactivity in CD and an opposite loss of reactivity in UC. Our results highlight previously unknown pathogenic properties of IgA in IBD that could support dysbiosis

    Human monocyte-derived suppressive cells (HuMoSC) for cell therapy in giant cell arteritis

    No full text
    This article is part of the Research Topic "Novel Therapeutic Options in Large Vessel Vasculitis".International audienceIntroduction The pathogenesis of Giant Cell Arteritis (GCA) relies on vascular inflammation and vascular remodeling, the latter being poorly controlled by current treatments. Methods This study aimed to evaluate the effect of a novel cell therapy, Human Monocyte-derived Suppressor Cells (HuMoSC), on inflammation and vascular remodeling to improve GCA treatment. Fragments of temporal arteries (TAs) from GCA patients were cultured alone or in the presence of HuMoSCs or their supernatant. After five days, mRNA expression was measured in the TAs and proteins were measured in culture supernatant. The proliferation and migration capacity of vascular smooth muscle cells (VSMCs) were also analyzed with or without HuMoSC supernatant. Results Transcripts of genes implicated in vascular inflammation ( CCL2 , CCR2 , CXCR3 , HLADR ), vascular remodeling ( PDGF , PDGFR ), angiogenesis (VEGF) and extracellular matrix composition ( COL1A1 , COL3A1 and FN1 ) were decreased in arteries treated with HuMoSCs or their supernatant. Likewise, concentrations of collagen-1 and VEGF were lower in the supernatants of TAs cultivated with HuMoSCs. In the presence of PDGF, the proliferation and migration of VSMCs were both decreased after treatment with HuMoSC supernatant. Study of the PDGF pathway suggests that HuMoSCs act through inhibition of mTOR activity. Finally, we show that HuMoSCs could be recruited in the arterial wall through the implication of CCR5 and its ligands. Conclusion Altogether, our results suggest that HuMoSCs or their supernatant could be useful to decrease vascular in flammation and remodeling in GCA, the latter being an unmet need in GCA treatment

    Neointimal myofibroblasts contribute to maintaining Th1/Tc1 and Th17/Tc17 inflammation in giant cell arteritis

    No full text
    International audienceVascular smooth muscle cells (VSMCs) have been shown to play a role in the pathogenesis of giant cell arteritis (GCA) through their capacity to produce chemokines recruiting T cells and monocytes in the arterial wall and their ability to migrate and proliferate in the neointima where they acquire a myofibroblast (MF) phenotype, leading to vascular stenosis. This study aimed to investigate if MFs could also impact T-cell polarization. Confocal microscopy was used to analyze fresh fragments of temporal artery biopsies (TABs). Healthy TAB sections were cultured to obtain MFs, which were then treated or not with interferon-gamma (IFN-Îł) and tumor necrosis factor-alpha (TNF-α) and analyzed by immunofluorescence and RT-PCR. After peripheral blood mononuclear cells and MFs were co-cultured for seven days, T-cell polarization was analyzed by flow cytometry. In the neointima of GCA arteries, we observed a phenotypic heterogeneity among VSMCs that was consistent with a MF phenotype (α-SMA + CD90 + desmin + MYH11 +) with a high level of STAT1 phosphorylation. Co-culture experiments showed that MFs sustain Th1/Tc1 and Th17/Tc17 polarizations. The increased Th1 and Tc1 polarization was further enhanced following the stimulation of MFs with IFN-Îł and TNF-α, which induced STAT1 phosphorylation in MFs. These findings correlated with increases in the production of IL-1ÎČ, IL-6, IL-12 and IL-23 by MFs. Our study showed that MFs play an additional role in the pathogenesis of GCA through their ability to maintain Th17/Tc17 and Th1/Tc1 polarizations, the latter being further enhanced in case of stimulation of MF with IFN-Îł and TNF-α

    Mucosal-associated invariant T cells in giant cell arteritis

    No full text
    International audienceThis study aimed to assess the implication of mucosal-associated invariant T (MAIT) cells in GCA. Blood samples were obtained from 34 GCA patients (before and after 3 months of treatment with glucocorticoids (GC) alone) and compared with 20 controls aged >50 years. MAIT cells, defined by a CD3(+)CD4(-)TCRγΎ(-)TCRVα7.2(+)CD161(+) phenotype, were analyzed by flow cytometry. After sorting, we assessed the ability of MAIT cells to proliferate and produce cytokines after stimulation with anti CD3/CD28 microbeads or IL-12 and IL-18. MAIT were stained in temporal artery biopsies (TAB) by confocal microscopy. MAIT cells were found in the arterial wall of positive TABs but was absent in negative TAB. MAIT frequency among total αÎČ-T cells was similar in the blood of patients and controls (0.52 vs. 0.57%; P = 0.43) and not modified after GC treatment (P = 0.82). Expression of IFN-Îł was increased in MAIT cells from GCA patients compared to controls (44.49 vs. 32.9%; P = 0.029), and not modified after 3 months of GC therapy (P = 0.82). When they were stimulated with IL-12 and IL-18, MAIT from GCA patients produced very high levels of IFN-Îł and displayed a stronger proliferation compared with MAIT from controls (proliferation index 3.39 vs. 1.4; P = 0.032). In GCA, the functional characteristics of MAIT cells are modified toward a pro-inflammatory phenotype and a stronger proliferation capability in response to IL-12 and IL-18, suggesting that MAIT might play a role in GCA pathogenesis. Our results support the use of treatments targeting IL-12/IL-18 to inhibit the IFN-Îł pathway in GCA

    Improvement of Treg immune response after treatment with tocilizumab in giant cell arteritis

    No full text
    International audienceOBJECTIVES: To study the percentage, suppressive function and plasticity of Treg in giant cell arteritis (GCA), and the effects of glucocorticoids and tocilizumab. METHODS: Blood samples were obtained from 40 controls and 43 GCA patients at baseline and after treatment with glucocorticoids + IV tocilizumab (n = 20) or glucocorticoids (n = 23). Treg percentage and phenotype were assessed by flow cytometry. Suppressive function of Treg was assessed by measuring their ability to inhibit effector T-cell (Teff) proliferation and polarisation into Th1 and Th17 cells. RESULTS: Treg (CD4(+)CD25(high)FoxP3(+)) frequency in total CD4(+) T cells was decreased in active GCA patients when compared to controls (2.5% vs. 4.7%, P < 0.001) and increased after treatment with tocilizumab but worsened after treatment with glucocorticoids alone. Treg lacking exon 2 of FoxP3 were increased in GCA patients when compared to controls (23% vs. 10% of total Treg, P = 0.0096) and normalised after treatment with tocilizumab + glucocorticoids but not glucocorticoids alone. In GCA patients, Treg were unable to control Teff proliferation and induced ˜50% increase in the amount of IL-17(+) Teff, which was improved after in vitro blockade of the IL-6 pathway by tocilizumab. CONCLUSION: This study reports quantitative and functional disruptions in the regulatory immune response of GCA patients and demonstrates that, unlike glucocorticoids, tocilizumab improves Treg immune response

    Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial

    No full text
    International audienc
    corecore