scholarly journals Inflammatory Signatures of Pathogenic and Non-Pathogenic Leptospira Infection in Susceptible C3H-HeJ Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Advait Shetty ◽  
Suman Kundu ◽  
Maria Gomes-Solecki
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Nk Cells ◽  
Inflammatory Cytokines ◽  
Low Income ◽  
Post Infection ◽  
Low Income Countries ◽  
Surveillance Systems ◽  
Pathogenic Leptospira ◽  
Phagocytic Response

The exact global impact of leptospirosis is unknown due to inadequate surveillance systems in place in most low-income countries. In this study, we analyzed the differences in mouse inflammatory signatures involved in pathogenic versus non-pathogenic Leptospira recognition at 24h and 72h post infection. Injection of C3H-HeJ mice with non-pathogenic L. biflexa increased circulation of a few chemokines (5/21, 24%) without secretion of cytokines in blood that resulted in engagement of resident macrophages, dendritic cells, neutrophils and NK cells without engagement of T cells. In contrast, pathogenic L. interrogans induced circulation of a much higher panel of chemokines (18/21, 86%) and pro- and anti-inflammatory cytokines (11/19, 58%) in blood with a resulting signaling cascade leading to engagement of macrophages, dendritic cells, monocytes, NK cells and T cells without engagement of neutrophils. Although neutrophils do not appear to be engaged, a considerable number of chemokines that recruit other granulocytes such as eosinophils and basophils were also increased at 72h post infection with L. interrogans. Overall, the data suggest that prevention of dissemination of L. biflexa is associated with an early engagement of the innate immune response characterized by upregulation of a few chemokines that results in an efficacious phagocytic response without an overwhelming increase of pro-inflammatory cytokines. However, when macrophages fail to clear a pathogenic serovar such as L. interrogans, the adaptive response (T cells) is engaged to help out, but the resulting chemo-cytokine storm mediates a robust but non-resolving inflammatory response to pathogenic Leptospira that results in dissemination, kidney colonization, pathology and disease.

Anti-GvHD Effect of Antithymocyte Globulin Is Mediated by Antibodies Binding to T Cells and Regulatory NK Cells, and Less So or Not at All by Antibodies Binding to Other Mononuclear Cell Subsets

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2346-2346
Author(s):  
Mette Hoegh-Petersen ◽  
Minaa Amin ◽  
Yiping Liu ◽  
Alejandra Ugarte-Torres ◽  
Tyler S Williamson ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Antithymocyte Globulin ◽  
Chronic Gvhd ◽  
Wilcoxon Test ◽  
Effector Memory

Abstract Abstract 2346 Introduction: Polyclonal rabbit-anti-human T cell globulin may decrease the likelihood of graft-vs-host disease (GVHD) without increasing the likelihood of relapse. We have recently shown that high levels of antithymocyte globulin (ATG) capable of binding to total lymphocytes are associated with a low likelihood of acute GVHD grade 2–4 (aGVHD) as well as chronic GVHD needing systemic therapy (cGVHD) but not increased likelihood of relapse (Podgorny PJ et al, BBMT 16:915, 2010). ATG is polyclonal, composed of antibodies for antigens expressed on multiple cell subsets, including T cells, B cells, NK cells, monocytes and dendritic cells. These cell subsets may play a role in the pathogenesis of GVHD. The anti-GVHD effect of ATG may be mediated through killing/inhibition of one or several of these cell subsets (eg, T cells) or their subsets (eg, naïve T cells as based on mouse experiments naïve T cells are thought to play a major role in the pathogenesis of GVHD). To better understand the mechanism of action of ATG on GVHD, we set out to determine levels of which ATG fraction (capable of binding to which cell subset) are associated with subsequent development of GVHD. Patients and Methods: A total of 121 patients were studied, whose myeloablative conditioning included 4.5 mg/kg ATG (Thymoglobulin). Serum was collected on day 7. Using flow cytometry, levels of the following ATG fractions were determined: capable of binding to 1. naïve B cells, 2. memory B cells, 3. naïve CD4 T cells, 4. central memory (CM) CD4 T cells, 5. effector memory (EM) CD4 T cells, 6. naïve CD8 T cells, 7. CM CD8 T cells, 8. EM CD8 T cells not expressing CD45RA (EMRA-), 9. EM CD8 T cells expressing CD45RA (EMRA+), 10. cytolytic (CD16+CD56+) NK cells, 11. regulatory (CD16-CD56high) NK cells, 12. CD16+CD56− NK cells, 13. monocytes and 14. dendritic cells/dendritic cell precursors (DCs). For each ATG fraction, levels in patients with versus without aGVHD or cGVHD were compared using Mann-Whitney-Wilcoxon test. For each fraction for which the levels appeared to be significantly different (p<0.05), we determined whether patients with high fraction level had a significantly lower likelihood of aGVHD or cGVHD than patients with low fraction level (high/low cutoff level was determined from ROC curve, using the point with maximum sum of sensitivity and specificity). This was done using log-binomial regression models, ie, multivariate analysis adjusting for recipient age (continuous), stem cell source (marrow or cord blood versus blood stem cells), donor type (HLA-matched sibling versus other), donor/recipient sex (M/M versus other) and days of follow up (continuous). Results: In univariate analyses, patients developing aGVHD had significantly lower levels of the following ATG fractions: binding to naïve CD4 T cells, EM CD4 T cells, naïve CD8 T cells and regulatory NK cells. Patients developing cGVHD had significantly lower levels of the following ATG fractions: capable of binding to naïve CD4 T cells, CM CD4 T cells, EM CD4 T cells, naïve CD8 T cells and regulatory NK cells. Patients who did vs did not develop relapse had similar levels of all ATG fractions. In multivariate analyses, high levels of the following ATG fractions were significantly associated with a low likelihood of aGVHD: capable of binding to naïve CD4 T cells (relative risk=.33, p=.001), EM CD4 T cells (RR=.30, p<.001), naïve CD8 T cells (RR=.33, p=.002) and regulatory NK cells (RR=.36, p=.001). High levels of the following ATG fractions were significantly associated with a low likelihood of cGVHD: capable of binding to naïve CD4 T cells (RR=.59, p=.028), CM CD4 T cells (RR=.49, p=.009), EM CD4 T cells (RR=.51, p=.006), naïve CD8 T cells (RR=.46, p=.005) and regulatory NK cells (RR=.55, p=.036). Conclusion: For both aGVHD and cGVHD, the anti-GVHD effect with relapse-neutral effect of ATG appears to be mediated by antibodies to antigens expressed on naïve T cells (both CD4 and CD8), EM CD4 T cells and regulatory NK cells, and to a lesser degree or not at all by antibodies binding to antigens expressed on B cells, cytolytic NK cells, monocytes or DCs. This is the first step towards identifying the antibody(ies) within ATG important for the anti-GVHD effect without impacting relapse. If such antibody(ies) is (are) found in the future, it should be explored whether such antibody(ies) alone or ATG enriched for such antibody(ies) could further decrease GVHD without impacting relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reciprocal Activating Interaction Between Dendritic Cells and Pamidronate-Stimulated γδ T Cells: Role of CD86 and Inflammatory Cytokines

2004 ◽  
Vol 174 (1) ◽  
pp. 252-260 ◽  
Author(s):  
Lucia Conti ◽  
Rita Casetti ◽  
Marco Cardone ◽  
Barbara Varano ◽  
Angelo Martino ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Inflammatory Cytokines ◽  
Γδ T Cells

Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3668-3674 ◽  
Author(s):  
Maria C. Kuppner ◽  
Anabel Scharner ◽  
Valeria Milani ◽  
Christoph von Hesler ◽  
Katharina E. Tschöp ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Human Monocyte ◽  
Glutathione Depletion ◽  
Intracellular Glutathione ◽  
Ifn Γ

AbstractIfosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-γ (IFN-γ) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-γ. The decrease in allostimulatory capacity and in IFN-γ and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function. (Blood. 2003;102: 3668-3674)

scholarly journals Apoptotic Cells for the Prevention of Cytokine Release Syndrome (CRS) in CAR T-Cell Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1626-1626
Author(s):  
Dror Mevorach ◽  
Veronique Amor ◽  
Yehudith Shabat
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Apoptotic Cells ◽  
Car T ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Abstract Background: Chimeric antigen receptor (CAR)-modified T cells with specificity against CD19 have demonstrated dramatic promise against highly refractory hematologic malignancies. Clinical responses with complete remission rates as high as 90% have been reported in children and adults with relapsed/refractory acute lymphoblastic leukemia (ALL). However, very significant toxicity has been observed and as many as 30% in average developing severe forms of CRS and possibly related neurotoxicity. CRS is occurring due to large secretion of pro-inflammatory cytokines, mainly from macrophages/monocytes, and resembles macrophage-activating syndrome and hemophagocytosis in response to CAR T-secreting IFN-g and possibly additional cytokines. To better understand the mechanisms leading to CRS and to treat or prevent it, we have developed in vitro and in vivo models of CRS with and without CAR-modified T cells. Early apoptotic cells that have been successfully tested for the prevention of acute GVHD, including in 7 ALL patients, were tested in these models for their effect on cytokines and CAR T cell cytotoxicity. Methods: CD19-expressing HeLa cells were used alone or with co-incubation with human macrophages for in vitro experiments and intraperitoneal experiments. Raji was used in vivo for leukemia induction. LPS and IFN-γ were used to trigger additional cytokine release. CD19-specific CAR-modified cells were used (ProMab) for anti-tumor effect against CD19-bearing cells. Cytotoxicity assay was examined in vivo using 7-AAD with flow cytometry and in vitro by survival curves and analysis of tumor load in bone marrow and liver. CRS occurred spontaneously or in response to LPS and IFN-γ. Mouse IL-10, IL-1β, IL-2, IP-10, IL-4, IL-5, IL-6, IFNα, IL-9, IL-13, IFN-γ, IL-12p70, GM-CSF, TNF-α, MIP-1α, MIP-1β, IL-17A, IL-15/IL-15R, and IL-7, as well as 32 human cytokines were evaluated by Luminex technology using the MAPIX system analyzer (Mereck Millipore) and MILLIPLEX Analyst software (Merek Millipore). Mouse IL-6Rα, MIG (CXCL9), and TGF-β1 were evaluated by Quantikine ELISA (R&D systems). Bone marrow and liver were evaluated using flow cytometry and immunohistochemistry. The IFN-γ effect was evaluated by STAT1 phosphorylation and biological products. Human macrophages and dendritic cells were generated from monocytes. Early apoptotic cells were produced as shown in GVHD clinical trial; at least 50% of cells were annexin V-positive and less than 5% were PI-positive. Results: Apoptotic cells had no negative effect in vitro or in vivo on CAR-modified T cells with specificity against CD19. There were comparable E/T ratios for CAR T in the presence or absence of apoptotic cells in vitro, and comparable survival curves in vivo. On the other hand, significant downregulation (p<0.01) of pro-inflammatory cytokines, including IL-6, IP-10, TNF-a, MIP-1α, MIP-1β, was documented. IFN-γ was not downregulated, but its effect on macrophages and dendritic cells was inhibited at the level of phosphorylated STAT1 and IFN-γ-induced expression of CXCL10 and CXCL9 was reduced. Conclusion: CRS evolves from several factors, including tumor biology, interaction with monocytes/macrophages/dendritic cells, and as a response to the CAR T cell effect and expansion. Apoptotic cells decrease pro-inflammatory cytokines that originate from innate immunity and inhibit the IFN-γ effect on monocyte/macrophages/ dendritic cells without harming IFN-γ levels or CAR-T cytotoxicity. Disclosures Mevorach: Enlivex: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Amor:Enlivex: Employment. Shabat:Enlivex: Employment.

KIR Genetics Modifies Susceptibility to Inflammatory Disorder by Reprogramming Human Natural Killer Cell Function

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3282-3282
Author(s):  
Chao Ma ◽  
Lin Lin ◽  
Henry Erlich ◽  
Elizabeth Trachtenberg ◽  
Stephan Targan ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Cytokines ◽  
Cd4 T Cells ◽  
Culture Media ◽  
Killer Cell ◽  
Cellular Mechanism ◽  
Activation Threshold ◽  
Pro Inflammatory Cytokines

Abstract Abstract 3282 Innate lymphocytes can play both protective and pathogenic roles in chronic inflammatory disorders. Recently, killer-cell immunoglobulin-like receptors (KIRs) and its cognitive ligands - human leukocyte antigen (HLA) class I molecules - were identified as genetic risk factors for Crohn's Disease (CD), a common inflammation symptom. Natural killer (NK) cells, the major KIR-expressing cell type, can be educated through KIR-HLA ligation. To uncover the cellular mechanism that determines CD susceptibility, we utilize a novel single-cell functional proteomics microchip and other highly-multiplexed assays (Ma, C. et al. Nature Medicine, 2011, 17, 738–743). We show that, in genetically pertinent individuals, natural killer (NK) cells are functionally reprogrammed to modulate the activation threshold of CD4+ T cells, a major cellular mediator of chronic inflammation. Genetic study of 455 CD patients bearing the AA haplotype identifies that the HLA-C1/C1 allotype, ligand of the KIR2DL3 receptor, is significantly enriched (p<0.0001). Moreover, when evaluating the secretion of 20 cytokines from single purified NK cells that are retrieved from the peripheral blood, we observe that NK cells expressing KIR2DL3 were strongly polarized to robustly produce a myriad of pro-inflammatory cytokines and chemoattractants in copious amounts. Comparing to those from other subjects, NK cells from HLA-C1/C1 subjects produce significantly increased level (p<0.05) of 11 soluble mediators, including TNF, INF-g, ILs, and CCLs. Furthermore, among all NK cells within the HLA-C1/C1 subjects, NK cells expressing KIR2DL3 receptors are the most potent to produce cytokines (2-log higher) and exhibit the highest polyfunctionality. These observations are also confirmed by intracellular staining and ELISA assay of NK cell culture media. Most importantly, the KIR-educated NK cells can strongly augment the activation and proliferation of CD4+ T cells. As shown in autologous NK and CD4+ T cell co-culture assay, CD4+ T cells proliferate aggressively in the presence of NK cells in a dose-dependent fashion (R2=0.99). NK surface costimulatory molecules blockage and NK-CD4+ T cells transwell-separation experiments indicate that this augmentation is not contact-dependent. On the other hand, NK cytokine depletion and ELISA essay of the co-culture media confirmed that soluble factors, such as ILs, IFN-g and TNF, activate CD4+ T cells. KIR2DL3 signaling-mediated education licenses NK cells the capacity to secrete large amounts of pro-inflammatory cytokines and chemokines, which in turn lowers activation threshold of CD4+ T cells and increases susceptibility to chronic inflammation disorders. Our study establishes, for the first time, an immunologic cellular mechanism that explains the KIR genetics-based susceptibility to CD and other chronic inflammatory syndromes. Disclosures: No relevant conflicts of interest to declare.

Longitudinal Peripheral Blood Lymphocyte Subsets Correlate with Decreased Disease Activity in Juvenile Dermatomyositis

2013 ◽  
Vol 40 (7) ◽  
pp. 1200-1211 ◽  
Author(s):  
Floranne C. Ernste ◽  
Cynthia S. Crowson ◽  
Consuelo Lopez de Padilla ◽  
Molly S. Hein ◽  
Ann M. Reed
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Disease Activity ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Juvenile Dermatomyositis ◽  
Plasmacytoid Dendritic Cells ◽  
Myeloid Dendritic Cells ◽  
Hla Dr ◽  
Vas Scores

Objective:To determine the clinical characteristics and subsets of peripheral blood lymphocytes (PBL), which correlate with decreased disease activity in patients with juvenile dermatomyositis (JDM).Methods.Peripheral blood mononuclear cells from 24 patients with JDM were collected at Mayo Clinic Rochester between 2007 and 2011. These were analyzed using fluorescence-activated cell sorting and flow cytometry. Clinical disease activity was determined by visual analog scales (VAS) collected in 2 consecutive visits and correlated with PBL subsets.Results.The change in CD3+CD69+ T cells correlated with the change in global VAS scores. The change in HLA-DR- CD11c+ myeloid dendritic cells also correlated with the change in extramuscular VAS scores. There were trends toward decreased levels of HLA-DR- CD11c+ cells with decreased muscle and global VAS scores, but these did not reach significance. The change in HLA-DR- CD123+ plasmacytoid dendritic cells negatively correlated with the change in muscle VAS scores. Although not statistically significant, decreased levels of CD3-CD16- CD56+ natural killer (NK) cells and HLA-DR- CD86+ myeloid dendritic cells, and increased levels of CD16+CD56- NK cells, correlated with decreased VAS scores.Conclusion.Changes in CD3+CD69+ T cells, HLA-DR- CD11c+ myeloid dendritic cells, and HLA-DR- CD123+ plasmacytoid dendritic cells are associated with improved clinical course in JDM and could be used as markers for disease activity, but findings need to be verified in a larger, independent cohort. Lack of significant differences among most of our PBL subsets suggests that lymphocyte phenotyping may be difficult to definitively correlate with disease activity in JDM.

537 Conventional type 1 dendritic cells and natural killer cells demonstrate strong correlation to T lymphocyte infiltration in cervical cancer tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A573-A573
Author(s):  
Anushka Dikshit ◽  
Xiao-jun Ma ◽  
Bingqing Zhang
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Strong Correlation ◽  
Tumor Antigens ◽  
Spatial Relationship ◽  
Conventional Type

BackgroundThe ability of T cells to mediate anti-tumor immunity has been harnessed to develop successful immunotherapies in recent years. Although direct presentation of tumor antigens by tumor cells plays an important role in the effector function of cytotoxic T lymphocytes (CTLs), cross-presentation by professional antigen presenting cells such as dendritic cells (DCs) is vital for priming naive CD8+ T cells and developing a sustainable cytotoxic response. Natural killer (NK) cells within the tumor microenvironment (TME) recruit a specific population of DCs called conventional type 1 DCs (cDC1s) into the TME by secreting chemokines such as CCL5 and XCL1. However, these cells are very low in abundance and are characterized by the expression of numerous markers, making their detection in the tissue context challenging.MethodsTherefore, to interrogate the presence of cDC1 and NK cells in the TME and reveal their spatial relationship we utilized the highly sensitive and specific RNAscope Multiplex Fluorescence in situ hybridization (ISH) assay. Probes for XCR1, THBD, CLEC9A, and CCR5 were used to identify cDC1 cells within 4 cervical cancer tumors. These tumors were then assessed for the presence of NK cells by using specific marker probes such as CD56 and NCR1 and chemokines XCL1 and CCL5. Finally, CTLs were visualized to determine if there is a correlation between the presence of cDC1 and NK cells and CTL infiltration within the cervical cancer tumors.ResultsOur results revealed a strong correlation between the presence of NK cells, cDC1 cells, and CTLs within 3 out of 4 cervical cancer samples. The NK cells showed expression of the chemokines XCL1 and CCL5, which are the ligands for XCR1 and CCR5 respectively, suggesting that the XCR1+/CCR5+ cDC1 cells may have been potentially recruited by these NK cells. Regions high in cDC1 and NK cells also showed significantly higher levels of CTL recruitment, as indicated by the presence of CD8+/IFNG+ T cells. Conversely, 1 of the 4 cervical cancer samples demonstrated relatively lower levels of NK cells which correlated with lower cDC1 cells and in turn lower CTL infiltration.ConclusionsIn conclusion, by utilizing the RNAscope Multiplex ISH assay we were able to identify and visualize the spatial relationship between NK cells, CTLs, and cDC1 cells, a rare subset of DC cells that excel at presenting tumor antigens to T cells. Using this technology, it is possible to spatially interrogate the TME and detect specialized immune cells when assessing response to immunotherapies.

Human CD4+ CD25high Regulatory T Cells Inhibit Myeloid but Not Plasmacytoid Dendritic Cells Activation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 767-767
Author(s):  
Roch Houot ◽  
Ivan Perrot ◽  
Isabelle Durand ◽  
Eric Garcia ◽  
Serge Lebecque
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Inflammatory Cytokines ◽  
Human Peripheral Blood ◽  
Cell Contact ◽  
Cytokines Secretion ◽  
Pro Inflammatory Cytokines

Abstract CD4+CD25+ regulatory T cells (Treg) are essential negative regulators of immune responses. However, the mechanisms of immune suppression and the spectrum of cells they target remain incompletely defined. In particular, although Treg directly suppress conventional T cells in vitro, they might also affect antigen presenting cells (APC). Here, we studied the maturation of human myeloid (mDC) and plasmacytoid (pDC) dendritic cells activated with Toll-like receptor (TLR) ligands in the presence of CD4+ CD25high regulatory T cells in vitro. T cells and DC subsets were purified from normal human peripheral blood. LPS, CpG ODN 2216 and R-848 were used to trigger the maturation of mDC, pDC or both through TLR4, TLR9 and TLR7/8 respectively. Preactivated CD4+ CD25high Treg had no effect on the maturation of pDC. Conversely, they strongly suppressed TLR-triggered mDC costimulatory molecules up-regulation, pro-inflammatory cytokines secretion and their antigen presentation capacity, as opposed to conventionnal T cells (Tconv). At a ratio of 3 Treg for 1 DC, the percentage of mDC acquiring CD80 was reduced 5 fold (from 75% to 16%) while the Mean Fluorescence Intensity was decreased by approximately 65% for CD80 and 35% for CD86 after LPS stimulation and by 50% and 20% after R-848 stimulation. Furthermore, Treg dramatically decreased the secretion of IL-12p40, TNF-α, and IL-6 by mDC (95%, 93% and 50% average inhibition respectively) after LPS activation and to a lesser but still significant extent (38%, 35%, and 38% average inhibition respectively) after R848 stimulation. Finally, we found that Treg-conditionned mDC had a reduced ability to trigger naïve T cell proliferation in a mixed leukocyte reaction. Suppression of mDC activation by Treg appeared to require cell-cell contact. Moreover, the inhibition of pro-inflammatory cytokines secretion, but not of phenotypic maturation, was almost completely restored using an anti-IL10 receptor monoclonal antibody, but not anti-TGFβ nor anti-CTLA-4 blocking antibodies. Those data suggest that Treg prevent the co-stimulatory molecules up-regulation on mDC through contact dependent mechanisms, while the modulation of cytokines secretion appears to be largely mediated by IL-10. Overall, our results provide the first evidence of a direct inhibition of human mDC but not pDC maturation by CD4+ CD25high Treg. Therefore, by restraining the maturation of mDC, human Treg may enlist those cells for the initiation and the amplification of tolerance in vivo.

scholarly journals Zoonotic Tuberculosis in Humans: Control, Surveillance, and the One Health Approach

2019 ◽  
Vol 41 (1) ◽  
pp. 130-144
Author(s):  
Rodrigo Macedo Couto ◽  
Otavio T Ranzani ◽  
Eliseu Alves Waldman
Keyword(s):  
Low Income ◽  
One Health ◽  
Control Strategies ◽  
Diagnostic Methods ◽  
Surveillance Data ◽  
Control Measures ◽  
Low Income Countries ◽  
Effective Control ◽  
Surveillance Systems ◽  
And Control

Abstract Zoonotic tuberculosis is a reemerging infectious disease in high-income countries and a neglected one in low- and middle-income countries. Despite major advances in its control as a result of milk pasteurization, its global burden is unknown, especially due the lack of surveillance data. Additionally, very little is known about control strategies. The purpose of this review was to contextualize the current knowledge about the epidemiology of zoonotic tuberculosis and to describe the available evidence regarding surveillance and control strategies in high-, middle-, and low-income countries. We conducted this review enriched by a One Health perspective, encompassing its inherent multifaceted characteristics. We found that the burden of zoonotic tuberculosis is likely to be underreported worldwide, with higher incidence in low-income countries, where the surveillance systems are even more fragile. Together with the lack of specific political commitment, surveillance data is affected by lack of a case definition and limitations of diagnostic methods. Control measures were dependent on risk factors and varied greatly between countries. This review supports the claim that a One Health approach is the most valuable concept to build capable surveillance systems, resulting in effective control measures. The disease characteristics and suggestions to implement surveillance and control programs are discussed.

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