Abstract 637: Hyperhomocysteinemia-mediated sCD40L induction and CD16 + CD40 + Monocyte Differentiation in Chronic Kidney Disease

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jiyeon Yang ◽  
Eric T Choi ◽  
Satya P Kunapuli ◽  
Xiaofeng Yang ◽  
Hong Wang
Keyword(s):  
Chronic Kidney Disease ◽  
T Cell ◽  
Kidney Disease ◽  
T Cell Activation ◽  
Cpg Island ◽  
Core Promoter ◽  
Flow Cytometric Analysis ◽  
Dna Hypomethylation ◽  
Activation Markers ◽  
Cd40 Gene

Chronic kidney disease (CKD) with uremia is associated with high mortality of cardiovascular disease (CVD) and Hyperhomocysteinemia (HHcy) is highly prevalent in uremic CKD patients. Elevated inflammatory monocyte (MC) is a cellular hallmark of chronic inflammation and CVD. Here we investigated mechanism in uremia-associated HHcy on MC differentiation in CKD-associated CVD. Data base mining revealed that CD40 is induced in MC from CKD subjects and associated with CVD, inflammatory disease and MC activation. Blood samples were obtained from 28 vascular disease patients with or without CKD. By flow cytometric analysis using CD14+ as a MC marker, we observed inflammatory CD16+ MC is increased in CVD, whereas CD40+ MC and CD16+CD40+ MC are increased in CKD-associated CVD. CD40+ MC expresses T cell activation markers CD86, HLA-DR, adhesion receptor CD62L, and chemokine receptor Ccr2. Plasma CD40L levels are increased in CVD, positively correlated with CD16+ MC. Interestingly, plasma Hcy levels are increased in CKD-associated CVD, positively correlated with cellular Hcy, plasma creatinine, CD16+CD40+ MC, and negatively correlated with S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH), an indicator of methylation. In addition, MC and T cell inflammatory cytokines TNFα, IL-6, and IFN[[Unable to Display Character: ɤ]] are induced in CKD-associated CVD subjects. Next, we examined mechanism of CD16+CD40+ MC differentiation using cultured human peripheral blood mononuclear cells (hPBMC). CKD serum, Hcy, and CD40L induced CD16+CD40+ MC differentiation, which were prevented by folic acid and CD40L antibody. IFN[[Unable to Display Character: ϫ]], TNFα, and IL-6 synergistically induced CD16+CD40+ MC differentiation, which was blocked by neutralizing antibodies to TNFα and IL-6. Hcy inhibited DNA methyltransferase 1 activity in isolated human blood MC. Finally, by gene analysis and pyrosequencing, we identified that the core promoter of CD40 gene is located at sole CpG island and hypomethylated at p65 consensus element in WBC from CKD-associated CVD subjects with low SAM/SAH ratio. In conclusion, we identified CD16+CD40+ MC as a novel inflammatory MC subset which is increased in uremic HHcy-associated CVD. CD16+CD40+ MC differentiation may be due to CD40 promoter DNA hypomethylation.

Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation

2018 ◽  
Vol 34 (11) ◽  
pp. 1853-1863 ◽  
Author(s):  
Ruifeng Wang ◽  
Titi Chen ◽  
Chengshi Wang ◽  
Zhiqiang Zhang ◽  
Xin Maggie Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kidney Injury ◽  
Public Health Problem ◽  
Global Public Health ◽  
Flt3 Inhibitor

Abstract Background Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. Methods To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. Results Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103− DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. Conclusion Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.

scholarly journals Expression of Chemokine Receptors on Peripheral Blood T Cells in Children with Chronic Kidney Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Maria Szczepańska ◽  
Łukasz Sędek ◽  
Irena Makulska ◽  
Krystyna Szprynger ◽  
Bogdan Mazur ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
T Lymphocytes ◽  
Conservative Treatment ◽  
Peripheral Blood ◽  
Chemokine Receptors ◽  
Flow Cytometric Analysis ◽  
T Cell Subsets

Chemokine receptors play a role in leukocyte recruitment, activation, and maintaining effector functions and regulate adaptive immune response and angiogenesis. The study aimed at flow cytometric analysis of T cell subsets with selected surface chemokine receptors (CCR4, CCR5, CCR7, CXCR3, and CXCR4) or receptor combination in peripheral blood of children with chronic kidney disease (CKD) on hemodialysis (HD). The percentage of T lymphocytes with CD8 and combined CD28,CCR7 expression was higher in HD children. The percentage of T lymphocytes expressing CCR7, CD28,CCR7, and CXCR4,CD8 was increased in children on conservative treatment. Total number (tn) of CXCR4+ cells was reduced in children on hemodialysis. The tn of T CXCR3+ cells was lower in children on conservative treatment. During HD the percentage of T CD4+ cells was higher and of T CXCR3+ lymphocytes was lower after HD session as compared to 15 min of session duration. During HD tn of T cells with expression of CCR4, CCR5, CCR7, CXCR3, and CXCR4 was constant. The alteration of chemokine receptors expression in children with CKD occurs early in the development. Diminished expression of CXCR3, CXCR4 on T cells in patients with CKD on HD might result in impaired inflammatory response. Increased CCR7+ T cell percentage could be responsible for the alteration of migration of cells into secondary lymphatic organs.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

scholarly journals Simian Immunodeficiency Virus Promoter Exchange Results in a Highly Attenuated Strain That Protects against Uncloned Challenge Virus

2004 ◽  
Vol 78 (3) ◽  
pp. 1080-1092 ◽  
Author(s):  
Philippe Blancou ◽  
Nicole Chenciner ◽  
Raphaël Ho Tsong Fang ◽  
Valérie Monceaux ◽  
Marie-Christine Cumont ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Infection ◽  
Simian Immunodeficiency Virus ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Parental Virus ◽  
Wild Type ◽  
Activation Markers ◽  
Challenge Virus ◽  
Immunodeficiency Virus

ABSTRACT Among the many simian immunodeficiency virus (SIV) immunogens, only live attenuated viral vaccines have afforded strong protection to a natural pathogenic isolate. Since the promoter is crucial to the tempo of viral replication in general, it was reasoned that promoter exchange might confer a novel means of attenuating SIV. The core enhancer and promoter sequences of the SIV macaque 239nefstop strain (NF-κB/Sp1 region from −114 bp to mRNA start) have been exchanged for those of the human cytomegalovirus immediate-early promoter (CMV-IE; from −525 bp to mRNA start). During culture of the resulting virus, referred to as SIVmegalo, on CEMx174 or rhesus macaque peripheral blood mononuclear cells, deletions arose in distal regions of the CMV-IE sequences that stabilized after 1 or 2 months of culture. However, when the undeleted form of SIVmegalo was inoculated into rhesus macaques, animals showed highly controlled viremia during primary and persistent infection. Compared to parental virus infection in macaques, primary viremia was reduced by >1,000-fold to undetectable levels, with little sign of an increase of cycling cells in lymph nodes, CD4+ depletion, or altered T-cell activation markers in peripheral blood. Moreover, in contrast to wild-type infection in most infected animals, the nef stop mutation did not revert to the wild-type codon, indicating yet again that replication was dramatically curtailed. Despite such drastic attenuation, antibody titers and enzyme-linked immunospot reactivity to SIV peptides, although slower to appear, were comparable to those seen in a parental virus infection. When animals were challenged intravenously at 4 or 6 months with the uncloned pathogenic SIVmac251 strain, viremia was curtailed by ∼1,000-fold at peak height without any sign of hyperactivation in CD4+- or CD8+-T-cell compartment or increase in lymph node cell cycling. To date, there has been a general inverse correlation between attenuation and protection; however, these findings show that promoter exchange constitutes a novel means to highly attenuate SIV while retaining the capacity to protect against challenge virus.

scholarly journals SARS-CoV-2-specific humoral and cellular immunity in renal transplant and haemodialysis patients treated with convalescent plasma

2020 ◽  
Author(s):  
Monika Lindemann ◽  
Adalbert Krawczyk ◽  
Sebastian Dolff ◽  
Margarethe Konik ◽  
Hana Rohn ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cell ◽  
Kidney Disease ◽  
Plasma Treatment ◽  
Kidney Transplant ◽  
Antiviral Treatment ◽  
T Cell Responses ◽  
Close Monitoring ◽  
Cell Responses ◽  
Alternative Treatment Option

AbstractBackgroundWhen patients with chronic kidney disease are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) they can face two specific problems: Virus-specific immune responses may be impaired and remdesivir, an antiviral drug described to shorten the time to recovery, is contraindicated. Antiviral treatment with convalescent plasma could be an alternative treatment option.MethodsIn this case series we present two kidney transplant recipients and two patients dependent on haemodialysis who were infected with SARS-CoV-2 and received convalescent plasma. Antibodies against the spike 1 protein of SARS-CoV-2 were determined sequentially by IgG ELISA and neutralization assay and specific T cell responses by interferon-gamma ELISpot.ResultsPrior to treatment, in three patients antibodies were undetectable by ELISA (ratio < 1.1), corresponding to low neutralizing antibody titers (≤ 1:40). One patient was also negative to the ELISpot and two showed weak responses. After convalescent plasma treatment we observed an increase of SARS-CoV-2-specific antibodies (IgG ratio and neutralization titer) and of specific T cell responses. After intermittent clinical improvement one kidney transplant recipient again developed typical symptoms at day 12 after treatment and received a second cycle of convalescent plasma treatment. Altogether, three patients clinically improved and could be discharged from hospital. However, one multimorbid female in her early eighties deceased.ConclusionsOur data suggest that the success of convalescent plasma therapy may only be temporary in patients with chronic kidney disease; which requires an adaptation of the treatment regimen. Close monitoring after treatment is needed for this patient group.

scholarly journals TRPM2 Is Not Required for T-Cell Activation and Differentiation

2022 ◽  
Vol 12 ◽  
Author(s):  
Niels C. Lory ◽  
Mikolaj Nawrocki ◽  
Martina Corazza ◽  
Joanna Schmid ◽  
Valéa Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Activation Markers

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

scholarly journals Endothelial Activation Markers in Anemic Non-Dialysis Chronic Kidney Disease Patients

2008 ◽  
Vol 110 (4) ◽  
pp. c244-c250 ◽  
Author(s):  
Tejas V. Patel ◽  
Bharati V. Mittal ◽  
Sai Ram Keithi-Reddy ◽  
Jeremy S. Duffield ◽  
Ajay K. Singh
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Endothelial Activation ◽  
Activation Markers

Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients

2018 ◽  
Vol 35 (4) ◽  
pp. 624-632 ◽  
Author(s):  
Thomas Crépin ◽  
Mathieu Legendre ◽  
Clémence Carron ◽  
Clément Vachey ◽  
Cécile Courivaud ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Immune Senescence ◽  
Thymic Output ◽  
Age Related ◽  
T Cell Expansion

Abstract Background Patients with chronic kidney disease (CKD) are more prone to develop premature age-related diseases. Data on immune senescence are scarce in CKD populations, except in end-stage renal disease and dialysis. We designed a longitudinal prospective study to evaluate immune senescence at different CKD stages and its influence on CKD patient outcomes. Methods Clinical and biological data collections were performed on 222 patients at different CKD stages [1–2 (n = 85), 4 (n = 53) and 5 (n = 84)]. Immune senescence biomarkers were measured by cytometry on T cells (CD28, CD57, CD45RA, CD31, γH2A.X) or by quantitative polymerase chain reaction [relative telomere length (RTL)] on peripheral blood mononuclear cells and analysed according to CKD stages and outcomes. Results CKD was associated with an increase in immune senescence and inflammation biomarkers, as follows: low thymic output (197 ± 25 versus 88 ± 13 versus 73 ± 21 CD4+CD45RA+CD31+ T cells/mm3), an increased proportion of terminally differentiated T cells (CD8+CD28−CD57+) (24 ± 18 versus 32 ± 17 versus 35 ± 19%) restricted to cytomegalovirus-positive patients, telomere shortening (1.11 ± 0.36 versus 0.78 ± 0.24 versus 0.97 ± 0.21 telomere:single copy ratio) and an increase in C-reactive protein levels [median 2.9 (range 1.8–4.9) versus 5.1 (27–9.6) versus 6.2 (3.4–10.5) mg/L]. In multivariate analysis, shorter RTL was associated with death {hazard ratio [HR] 4.12 [95% confidence interval (CI) 1.44–11.75]}. Low thymic output was associated with infections [HR 1.79 (95% CI (1.34–9.58)] and terminally differentiated CD8+ T-cell expansion with a risk of cardiovascular events [CEs; HR 4.86 (95% CI 1.72–13.72)]. Conclusion CKD was associated with premature immune ageing. Each of these alterations increased the risk of specific age-related diseases, such as RTL and death, thymic function and infections and terminally differentiated CD8+ T-cell expansion and CEs.

Abstract 11697: Hyperhomocysteinemia Induces CD40 + Monocyte and Inflammatory Monocyte in Chronic Kidney Disease Subjects via DNA Hypomethylation-Related Mechanism

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jiyeon Yang ◽  
Abhigna C Kolli ◽  
Eric T Choi ◽  
Xiao-Feng Yang ◽  
Hong Wang
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Blood Cells ◽  
Healthy Donor ◽  
Methylation Status ◽  
Phenotypic Characterization ◽  
Dna Hypomethylation ◽  
Rt Pcr ◽  
Inflammatory Monocyte ◽  
Cd40 Expression

Hyperhomocysteinenia (HHcy) is associated with chronic kidney disease (CKD) which has increased cardiovascular disease (CVD) mortality and mobility. Elevated inflammatory monocyte (inf. MC) is a cellular hallmark of chronic inflammation which contributes to the burden CVD. We previously reported that HHcy induces inf. MC differentiation in mice and DNA hypomethylation in vascular cells. We assesses whether HHcy causes MC differentiation in CKD and the underlying mechanism. Degree of CKD was determined by plasma creatinine from patients with peripheral vascular disease (VD). Estimated glomerular filtration rate was calculated with modification in age, race and gender. (VD, n=13; VD with CKD, n=13; Healthy donor without evidence of VD and CKD, n=13). Blood cells were assessed for phenotypic characterization by flow cytometry. We found that plasma Hcy levels are elevated in VD and CKD. CD14++CD16+ inf. MC are increased in VD subjects and mild HHcy(>15μM). Plasma Hcy levels are positively correlated with inf. MC, CD40, TNF receptor family 5. We identify that CKD patient serum and Hcy (50μM) treatment increased CD40 in purified human blood MC by RT-PCR. Hcy metabolites, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), are increased in CKD subjects. SAM/SAH ratio, an indicator of methylation status, is reduced and is negatively correlated with Hcy, inf. MC, and CD40+ inf. MC. Hcy induced MC-origin inflammatory cytokines IL-6 mRNA in MC isolated from healthy donor by RT-PCR, and potentiated inflammatory cytokine IL-6, TNFα, and IFN[[Unable to Display Character: &#612;]]-induced CD40 expression in cultured PBMCs. Hcy suppressed CD40 transcription and reduced DNA methyltransferase 1 protein levels in cultured human MC. We identified four DNA hypomethylation CpG dinucleotides at p65 and PU.1 transcription factor consensus sequences on CD40 promoter in white blood cells isolated from CKD patients by Bisulfite pyrosequencing. Finally, CD40L levels are positively correlated with plasma Hcy and inf. MC. CD40 ligation by CD40L treatment (0.4μg/l) in peripheral blood mononuclear cells (PBMC) induced inf. MC differentiation. We conclude that HHcy potentiates IFN[[Unable to Display Character: &#612;]]-mediated CD40 expression via CD40 DNA hypomethylation in CKD and promotes CD40-CD40L mediated inf. MC differentiation.

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