B-Cell Lymphopenia and Circulating Neoplastic B-Cell Populations Are Associated with High Risk Disease in DLBCL: Results from the UK Remodl-B Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2669-2669
Author(s):  
Ruth Mary de Tute ◽  
Sharon Barrans ◽  
Andy C. Rawstron ◽  
Christopher T Manbridge ◽  
Josh Caddy ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
T Cell Subsets ◽  
Neoplastic Cells ◽  
Cell Counts ◽  
The Uk ◽  
Circulating Neoplastic Cells ◽  
The Impact

Abstract Background: Preliminary results from the UK REMoDL-B trial have shown that circulating neoplastic B-cells and B-lymphopenia are frequently detected by flow cytometry in presenting DLBCL patients. Uncertainty remains about the significance of these findings and how they relate to the course of clinical disease. Aim: The aim of this study was to assess whether numerical and phenotypic peripheral B-cell abnormalities are related to advanced disease and adverse prognosis. Methods: The study was carried out using peripheral blood samples collected from patients prior to first treatment. Peripheral blood was analysed using a panel of antibodies comprising of a CD19 and CD20 backbone, with Kappa, Lambda, CD5, CD45, CD49d, LAIR-1, CXCR5, CD31, CD95, CD38 and CD10, supplemented in some cases by CD81, CD79b, and CD43. Analysis allowed B-cell enumeration, identification of monoclonal populations and phenotypic classification as CLL, germinal centre (GC), non-GC or not otherwise specified (NOS) where the phenotype was indeterminate. In addition, gene expression profiling (GEP) was performed on the diagnostic tissue biopsy (FFPE) using the Illumina WG-DASL assay to classify tumours as GCB-type, ABC-type or unclassified. Results: A total of 845 patients with an average age of 62.7 years (range 20.9-87.8) were included. A monoclonal population was detected in 174/845 (20.5%) of cases; CLL 3%, GC 7.8%, non-GC 7.7% and NOS 2.1%. Numerical abnormalities were also detected; 33% of patients had B-lymphopenia (<0.06 x 109/l) and 2.8% had B-lymphocytosis (>1 x 109/l). There was minimal overlap between numerical abnormalities and the presence of neoplastic B-cells, with 86% of cases with an abnormal population having a normal B-cell count. Circulating neoplastic cells were present in a small proportion of cases with B-lymphopenia (17/264) and a higher percentage of cases with B-lymphocytosis (8/19), as would be expected. Neoplastic B-cells were detected in 33% of cases an International Prognostic Index (IPI) score of 4-5, compared to 14% of cases with an IPI of 0-2. B-lymphopenia was present in 39% of individuals with an IPI of 4-5 compared to 24% of individuals with an IPI of 0-2. 51% (58/113) of cases with BM involvement had a circulating monoclonal population, compared to 15% (116/732) of cases with no overt marrow disease. Conversely, 66% of cases with circulating neoplastic cells did not have marrow involvement but this may, in part, be a sensitivity issue as staging was based on morphological assessment only. Tumour GEP results were available for 690 individuals; 362 (52%) GCB, 184 (26%) ABC and 144 (21%) unclassified. 86% of populations identified in the ABC subgroup were phenotyped non-GC or NOS. Presence of a GC-population by flow was highly predictive of GCB GEP (88% GC-type populations detected were GCB cases). The number of discordant cases and CLL clones detected approximated to the numbers that would have been expected in a normal age-matched population. Conclusion: Both the presence of circulating monoclonal B-cells and B-lymphopenia showed an association with higher risk disease. In addition, there was strong concordance between clonal phenotypes and the GEP of the underlying tumours. It is likely that in most cases the peripheral clonal populations are circulating tumour cells or a closely related precursor clone. Absolute B-cell counts are known to decline with age but there was no correlation with age in this patient group. Immuosuppression has a role in the pathogenesis of DLBCL in the elderly and the observed B-lymphopenia may be as a result of underlying immune dysfunction. Alternatively it may reflect suppression of normal B-cells by the neoplastic clone. Either way this has implications for the efficacy of immunomodulatory drugs, especially if the T-cell subsets are also affected. Multiparameter flow is highly applicable for diagnostic screening of both numerical and phenotypic B-cell abnormalities and may have a role in the prognostic assessment of DLBCL. Outcome data will be available shortly allowing the impact on progression free overall survival to be assessed. Disclosures Rawstron: Celgene: Honoraria; Abbvie: Honoraria; Pharmacyclics: Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria; BD Biosciences: Patents & Royalties. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding. Davies:Seattle Genetics: Research Funding; Takeda: Honoraria. Jack:Jannsen: Research Funding.

B-cell and T-cell values in peripheral blood in Polish mixed-breed rabbits with addition of blood of meet breeds

2014 ◽  
Vol 17 (3) ◽  
pp. 421-426 ◽  
Author(s):  
B. Tokarz-Deptuła ◽  
P. Niedźwiedzka-Rystwej ◽  
B. Hukowska-Szematowicz ◽  
M. Adamiak ◽  
A. Trzeciak-Ryczek ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Laboratory Animals ◽  
Immunological Parameters ◽  
Four Seasons ◽  
Mixed Breed ◽  
The Impact

Abstract In Poland, rabbit is a highly valued animal, due to dietetic and flavour values of its meat, but above all, rabbits tend to be commonly used laboratory animals. The aim of the study was developing standards for counts of B-cells with CD19+ receptor, T-cells with CD5+ receptor, and their subpopulations, namely T-cells with CD4+, CD8+ and CD25+ receptor in the peripheral blood of mixed-breed Polish rabbits with addition of blood of meet breeds, including the assessment of the impact of four seasons of the year and animal sex on the values of the immunological parameters determined. The results showed that the counts of B- and T-cells and their subpopulations in peripheral blood remain within the following ranges: for CD19+ B-cells: 1.05 - 3.05%, for CD5+ T-cells: 34.00 - 43.07%, CD4+ T-cells: 23.52 - 33.23%, CD8+ T-cells: 12.55 - 17.30%, whereas for CD25+ T-cells: 0.72 - 2.81%. As it comes to the season of the year, it was observed that it principally affects the values of CD25+ T-cells, while in the case of rabbit sex, more changes were found in females.

scholarly journals B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5571-5579 ◽  
Author(s):  
Susan Moir ◽  
Clarisa M. Buckner ◽  
Jason Ho ◽  
Wei Wang ◽  
Jenny Chen ◽  
...  
Keyword(s):  
B Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
B Cell ◽  
Immune Cell ◽  
Memory B Cells ◽  
Early Initiation ◽  
Cell Counts ◽  
The Impact ◽  
Chronic Hiv Infection

Abstract Characterization of lymphocytes including B cells during early versus chronic HIV infection is important for understanding the impact of chronic viremia on immune cell function. In this setting, we investigated B cells before and after reduction of HIV plasma viremia by antiretroviral therapy (ART). At baseline, peripheral blood B-cell counts were significantly lower in both early and chronic HIV-infected individuals compared with uninfected controls. Similar to CD4+ but not CD8+ T cells, B-cell numbers in both groups increased significantly after ART. At baseline, B cells of early HIV-infected individuals were composed of a higher percentage of plasmablasts and resting memory B cells compared with chronic HIV-infected individuals whose B cells were composed of a higher percentage of immature/transitional and exhausted B cells compared with their early infection counterparts. At 1 year after ART, the percentage of resting memory B cells remained higher in early compared with chronic HIV-infected individuals. This difference translated into a better functional profile in that memory B-cell responses to HIV and non-HIV antigens were superior in early- compared with chronic-treated HIV infected individuals. These findings provide new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage.

HuMax-CD20 Fully Human Monoclonal Antibody in Follicular Lymphoma. First Human Exposure: Early Results of an Ongoing Phase I/II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1400-1400 ◽  
Author(s):  
Anton Hagenbeek ◽  
Torben Plesner ◽  
Jan Walewski ◽  
Andrzej Hellmann ◽  
Brian K. Link ◽  
...  
Keyword(s):  
B Cells ◽  
Adverse Events ◽  
B Cell ◽  
Cell Count ◽  
Peripheral Blood ◽  
Tumor Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Counts ◽  
Grade 3

Abstract HuMax-CD20 is a fully human monoclonal IgG1 antibody targeting a unique extracellular epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mouse tumor models more efficiently than Rituximab®, and i.v. infusion of HuMax-CD20 in cynomolgus monkeys has led to profound, long lasting, dose-dependent B-cell depletion. A total of 40 patients with CD20+ relapsed or refractory follicular non-Hodgkin’s lymphoma grade I-II will be enrolled in this open-label, dose-escalating, international, multi-center clinical trial. Cohorts of 10 patients will receive i.v. infusions at doses of either 300, 500, 700 or 1000 mg once weekly for 4 weeks. The patients are followed for 12 months. Patients receive oral acetaminophen and i.v. antihistamin before infusion. In case of adverse events of CTC grade 3 or higher, i.v. glucocorticosteroids are given. The endpoints are CT scan verified tumor response according to the Cheson criteria, B-cell depletion in peripheral blood and lymph nodes, time to next anti-lymphoma treatment, duration of response, BCL2 conversion, pharmacokinetics, and adverse events. Tumor and bone marrow biopsies and CT scans are assessed centrally. The first 17 patients treated with HuMax-CD20 are the subject of this report. Mean age is 60 years. In the 300 mg group all 10 patients have received all 4 infusions. Seven patients have been enrolled in the 500 mg group; three of them have received 4 infusions, two have received 3 infusions, and two patients have received 2 infusions. Baseline B-cell count was in the range of 11-382 x 106 cells per L with a median of 114 x 106. One week after the first infusion the median B-cell count available in 16 patients was 8 x 106 cells per L with a range of 0–19 x 106. In six of the 16 patients no B-cells were detected. B-cell counts measured one week after the 4th infusion are available for 10 patients. Eight patients had no detectable B-cells, one patient had 11 x 106 and one had 34 x 106 cells per L. B-cell counts eight weeks after the 4th infusion are available for two patients. No B-cells were detectable in these two patients. No dose limiting toxicity has been reported with administration of 300 or 500 mg. One serious adverse event assessed as not related to HuMax-CD20 has been reported in the 300 mg group. Infusion related adverse events have primarily been seen during the first infusion of HuMax-CD20. The events have, as expected, predominantly been signs and symptoms of cytokine release, e.g. pruritus, dyspnoea, rigors/chills, nausea, hypotension, urticaria, fatigue, fever and rash. In 15 of the 17 patients, 51 adverse events have been reported. Nine adverse events were CTC grade 3, 16 were grade 2, and 26 events were grade 1. In conclusion, this analysis based on preliminary data for the first 17 patients treated with HuMax-CD20 demonstrated significant depletion of peripheral blood B-cells and a favorable safety profile. An updated report of results for all 40 patients including preliminary tumor response data will be presented.

scholarly journals Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease

2021 ◽  
Vol 9 (2) ◽  
pp. e1125
Author(s):  
Rui Li ◽  
Thomas Francis Tropea ◽  
Laura Rosa Baratta ◽  
Leah Zuroff ◽  
Maria E. Diaz-Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Parkinson Disease ◽  
B Cell ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Cell Counts

Background and ObjectivesThere has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls.MethodsPeripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses.ResultsThe discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality.DiscussionOur findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

Evidence for Differential Regulation of Transferrin Receptor 1 in Normal vs. Malignant B Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3722-3722
Author(s):  
Ioanna Chiotoglou ◽  
Tatjana Smilevska ◽  
Kostas Stamatopoulos ◽  
Maria Samara ◽  
Sophia Likousi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Fluorescence Intensity ◽  
Peripheral Blood ◽  
Transferrin Receptor ◽  
Differential Regulation ◽  
Mrna Levels ◽  
Neoplastic Cells ◽  
Transferrin Receptor 1

Abstract Transferrin receptor 1 (TfR1, CD71) expression is related to the proliferative state of the cells as well as the induction of differentiation; furthermore, CD71 is one of the “classical” activation markers up-regulated upon B-cell activation. As we have recently shown (Smilevska et al., Leuk Res 2005, in press), CLL is characterized by almost uniformly high CD71 expression, regardless of IGH mutational load; this is in keeping with the activated status of neoplastic cells. In the present study, we evaluated TfR1 expression at the mRNA and protein level in CD19+ B cells sorted from peripheral blood mononuclear cells of two healthy donors, 37 patients with typical chronic lymphocytic leukemia (CLL), as well as the BV173 (B cell acute lymphoblastic leukemia) and EHEB (human chronic B cell leukemia) cell lines. In all CLL cases, the tumor load was at least 70%. Twenty-two out of 37 CLL cases (59%) carried IGHV genes with &lt;98% homology to the closest germline gene (“mutated”); the remainder (15/37, 41%) carried “unmutated” IGHV genes. TfR1 cDNA sequences were detected by RT-PCR in all cell samples using primers specific for TfR1 gene exons 15–17. Real-time PCR analysis (using h-HPRT as a housekeeping gene) revealed low TfR1 mRNA transcripts in both cell lines (relative TfR1/h-HPRT ratios for BV173/EHEB cells: 0.05/0.08), contrasting normal peripheral blood CD19+ B cells, which on average had a 1-log higher concentration (relative TfR1/h-HPRT ratios: 0.995). TfR1 mRNA levels were widely divergent in CLL samples (relative TfR1/h-HPRT ratios: 0.23–13.3); no statistically significant associations were identified with IGH mutation status. Cell lysates were separated by SDS-polyacrylamide gel electrophoresis, electroblotted onto the nitrocellulose filters for probing with anti-TfR1-specific antibody and actin polyclonal antibody (control); quantitative gel banding densitometry was performed using with Epson GT-8000 Laser scanner. TfR1 protein levels were similar in CD19+ peripheral blood normal B cells as well as malignant cell lines (CD19: 1.16, BV173: 1.16, EHEB: 1.12), although CLL samples showed greater individual variation (0.4–2); median values were not different from either normal B cells or B cell lines. CD71 expression was also studied by flow cytometry in 20/37 CLL cases; all analyzed cases were CD71-positive with a generally high percentage of CD71-expressing neoplastic cells (median 91%, range: 28.3–100.0%); based on staining intensity, 18/20 CD71 (+) cases had bright fluorescence intensity, whereas the remainder (2/20) had low fluorescence intensity (dim). These results allude to differential regulation of TfR1 expression in normal vs. malignant B cells. In normal B cells, transcriptional mechanisms exert an important control over TfR1 expression. In malignant B cells (primary cells or established cell lines), similar levels of TfR1 (CD71) protein in the context of widely divergent TfR1 mRNA levels might be attributed to the operation of post-transcriptional mechanisms (perhaps increased mRNA stability).

Patients With DLBCL Commonly Have B-Cell Lymphopenia and Circulating Clonal B-Cell Populations With a Phenotype Concordant With The Underlying Tumour

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3013-3013
Author(s):  
Ruth M de Tute ◽  
Sharon Barrans ◽  
Andy C. Rawstron ◽  
Peter W.M. Johnson ◽  
Andrew J Davies ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Peripheral Blood ◽  
Expression Profiling ◽  
Common Finding ◽  
Cell Populations ◽  
The Impact

Abstract Clonal B-cell populations with either a CLL or a non-CLL phenotype are a common finding in normal individuals but uncertainty remains about how this relates to the development of clinically significant disease. The aim of this study was to investigate the frequency of peripheral blood clonal B-cell populations and B-cell subset abnormalities in newly presenting DLBCL patients and to determine whether the incidence of these abnormalities differed between the GCB and ABC subtypes, which are regarded as having distinct pathogenesis. The study was carried out using peripheral blood samples collected from patients entered in the UK-REMoDL-B trial. This trial is testing the hypothesis that the ABC subtype of DLBCL responds preferentially to R-CHOP- Bortezomib. Gene expression profiling is performed on the diagnostic tissue biopsy (FFPE) using the Illumina WG-DASL assay prior to randomisation classified as GCB, ABC or unclassified (UN). The availability of GEP data allows meaningful comparison with the phenotype of clonal populations detected by flow cytometry. Peripheral blood taken prior to first treatment was analysed using multi-colour flow cytometry. Following red cell lysis with ammonium chloride, samples were incubated with a panel of antibodies comprising of a CD19 and CD20 backbone, with Kappa, Lambda, CD5, CD45, CD49d, LAIR-1, CXCR5, CD31, CD95, CD38 and CD10, supplemented in some cases by CD81, CD79b, and CD43. A minimum of 500,000 events were acquired on a FacsCanto II flow cytometer (Becton Dickinson). B-cells were enumerated and any monoclonal populations identified were classified as CLL, germinal centre (GC), non-GC or not otherwise specified (NOS) where the phenotype was indeterminate. 358 samples were eligible for inclusion from patients with an average age of 62.2years (range 22.9-86.1). Abnormalities were detected in 52% of cases (B-lymphopenia ((<0.06 x 109/l) 33%, B-lymphocytosis (>1 x 109/l) 2.8%, CLL clone 3.6%, GC clone 9.8%, non-GC clone 9.8%, clonal population NOS 2.2%). Gene expression profiling results were available for 278 individuals; 51% GCB, 32% ABC and 17% unclassified. The relationship between peripheral blood B-cell findings and the GEP determined phenotype of the tumour is shown in the table:TableB-lymphopeniaCLL CloneMonoclonal GC typeMonoclonalNon-GC typeMonoclonal NOSNormalB-cellGCB n=14241/142 (29%)5/142 (3.5%)21/142 (15%)8/142 (5.6%)2/142 (1%)72/142 (51%)ABC n=8927/89 (30%)2/89 (2%)2/89 (2%)12/89 (13.5%)2/89 (2%)49/89 (55%)Unclassified n=4726/47 (55%)0/50 (0%)2/47 (4%)6/47 (12%)6/47 (5%)14/47 (30%) In patients where clonal populations were detected in the peripheral blood there was striking concordance between the phenotype of the clone and the GEP of the underlying tumour. Presence of a GC-population by flow was highly predictive of GCB GEP (84% GC–type populations detected were in GCB cases). The number of discordant cases and the number of CLL clones detected approximate to the numbers that would be expected in a normal population of a similar age. It is, therefore, likely that in most cases circulating tumour cells or a closely related precursor clone are being detected. The similarity between the results of the ABC and unclassified GEP groups suggest that these are biologically related. An unexpected finding in this study was the high incidence of B-lymphopenia at a level that might be expected to be associated with increased risk of infection. This may reflect suppression of normal B-cells by the neoplastic clone or be a marker of underlying immune dysfunction that may predispose to the development of the tumour. Immuosuppression has a role in the pathogenesis of DLBCL in the elderly and this study suggests that this may also be a factor in the wider patient population. These results may have implications for prognostic assessment and may offer opportunities for early diagnosis and possibly response assessment in some patients. The impact on outcome will be assessed in the course of the trial. Disclosures: Jack: Roche /Genentech: Research Funding.

scholarly journals Immunological Consequences of Lenalidomide with and without Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3070-3070
Author(s):  
Jake A. Kloeber ◽  
Teresa K. Kimlinger ◽  
Jessica L. Haug ◽  
Kimberly J. Henderson ◽  
S.Vincent Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Nk Cell ◽  
Single Agent ◽  
Cell Populations ◽  
Newly Diagnosed

Introduction: Recent advancements in the treatment of multiple myeloma (MM) have centered on engaging the immune system to target multiple myeloma cells. Although these therapies are being combined with immunomodulatory imide drugs (IMiDs) and corticosteroids, the individual contributions of these drugs on the immune system of MM patients has not been examined in the upfront setting. In this study, we examined the peripheral blood immunophenotypes of newly diagnosed multiple myeloma (NDMM) patients receiving the IMiD lenalidomide with or without the corticosteroid dexamethasone. Methods: To characterize immunophenotypes, we utilized flow cytometry to profile white blood cell populations from 35 patients enrolled in a clinical trial testing the efficacy of lenalidomide with and without dexamethasone in NDMM (NCT00772915). In this trial, all patients were initiated on single-agent lenalidomide. Dexamethasone was initiated in patients that did not meet desirable responses or for disease progression. At each cycle, peripheral blood was stained with a 17-marker antibody panel against several immune lineages and functional surface markers. We grouped patients into two groups: 1) lenalidomide alone or 2) lenalidomide with dexamethasone according to their treatment regimen at each cycle timepoint. Results: First we confirmed anti-myeloma cell activity for both groups by measuring a steady decline in circulating plasma cells in both groups. Examining peripheral blood immunophenotypes showed an expected decrease in T cells and a smaller decrease in B cells in both groups of patients. Closer inspection of B cell populations revealed a switch towards a more immature B cell phenotype in both treatment groups. This was measured as a switch from CD19-CD20+ cells to CD19+CD20- B cells. Inspection of T cell subsets revealed that patients receiving single-agent lenalidomide had a sustained decrease in the levels of CD4+ T cells and increase in the levels of CD8+ T cells. This was seen in both naïve and regulatory T cells evidenced by a decrease in the CD4/CD8 ratio among CD28+ T cells as well as CD25+ T cells. Importantly, this alteration did not lead to sustained alterations in the overall level of CD25+ or CD28+ T cells, and the addition of dexamethasone reverses this trend. In addition to the effects seen on T and B cell numbers, we detected expansions of NK cell populations in patients receiving lenalidomide alone. This expansion is detected as an overall increase in CD56+ mononuclear cells with the majority of cells being CD56+CD3- cells. Conclusions: Our data show that lenalidomide and dexamethasone therapy have shared but distinct effects on peripheral blood immunophenotypes in NDMM. Both drugs alter B cells numbers and populations leading to an expansion of CD19+CD20- B cells. However, lenalidomide alone decreases the CD4/CD8 T cell ratio; and, lenalidomide more strongly expands NK cell populations. The addition of dexamethasone reverses this trend and leads to a restoration of the CD4/CD8 ratio. This suggests that lenalidomide without dexamethasone might be counterproductive in immunotherapies intended to recruit CD4+ T cells. Conversely, lenalidomide alone could increase the efficacy of immunotherapies dependent on NK cell recruitment such as antibody-dependent cellular cytotoxicity (ADCC). This information may benefit future investigations of immune responses in MM patients and improve the adoption of immunotherapies to MM patients. Figure Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals POS0387 ACPA STATUS CORRELATES WITH DIFFERENTIAL IMMUNE PROFILE OF RHEUMATOID ARTHRITIS PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 423.2-424
Author(s):  
A. Floudas ◽  
M. Canavan ◽  
T. McGarry ◽  
V. Krishna ◽  
S. Nagpal ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Synovial Tissue ◽  
Peripheral Blood ◽  
Flow Cytometric Analysis ◽  
Algorithm Analysis ◽  
Treat To Target ◽  
Tnf Α ◽  
Acpa Status

Background:Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20-30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Elucidating the underlying mechanisms of disease pathogenesis could inform a treat to target approach for both ACPA-positive and ACPA-negative RA patients.Objectives:To identify peripheral blood and synovial tissue immune population differences that associate with RA disease endotype.To identify unique RA patient synovial tissue gene signatures and enriched pathways that correlate with ACPA status.Methods:Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis of ACPApos and ACPAneg RA patient peripheral blood and synovial tissue single cell suspensions. Ex vivo peripheral blood and synovial tissue T cell stimulation and cytokine production characterisation. RNAseq analysis with specific pathway enrichment analysis of APCApos and ACPAneg RA patient synovial tissue biopsies.Results:Detailed profiling based on high dimensionality flow cytometric analysis of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells, T peripheral helper cells (Tph) and CD4 T cell proinflammatory cytokine responses with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. ACPApos RA patients were characterised by significantly (*P=0.03) increased frequency of Tfh (CXCR5+CD4+) cells and distinct clustering influenced by increased switched (IgD-CD27+) and DN (IgD-CD27-) memory B cells compared to APCAneg RA patients. Surprisingly synovial tissue B cell subpopulation distribution was similar between ACPAneg and ACPApos RA patients, with significant accumulation of switched and double negative memory B cells, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue CD4 T cell proinflammatory cytokine (TNF-α, IFN-γ, IL-2, GM-CSF, IL-17A, IL-22, IL-4) production was markedly different between ACPAneg and APCApos RA patients with hierarchical clustering and PCA analysis revealing endotype specific cytokine profiles with ACPAneg RA patient synovial T cells showing increased TNF-α (P=0.01) expression. RNAseq analysis of RA patient synovial tissue revealed significant disease endotype specific gene signatures with specific enrichment for B cell receptor signalling and T cell specific pathways in ACPApos compared to ACPAneg RA patients. Additionally, significantly different chemokine receptor expression based on RA patient ACPA status was observed with increased CXCR3 (P<0.001), CCR7 (P=0.002), and CCR2 (P=0.004) but decreased CXCR7 (P=0.007) expression in APCApos compared to ACPAneg RA patient synovial biopsies.Conclusion:ACPA status associates with unique synovial tissue immune cell and gene profile signatures highlighting differences in the underlying immunological mechanisms involved, therefore reinforcing the need for a treat to target approach for both endotypes of RA.Figure 1.RNAseq analysis of synovial tissue biopsies revealed specific T cell related pathway enrichment in ACPA positive compared to ACPA negative RA patients (n=50, analysis performed with the DESq2 and pathfindeR pipelines in R).Disclosure of Interests:Achilleas Floudas: None declared, Mary Canavan: None declared, Trudy McGarry Employee of: Novartis, Vinod Krishna Employee of: Janssen, Sunil Nagpal Employee of: Janssen, GSK, Douglas Veale Speakers bureau: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Consultant of: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Grant/research support from: Janssen, Abbvie, Pfizer, UCB, Ursula Fearon Speakers bureau: Abbvie, Grant/research support from: Janssen, Abbvie, Pfizer, UCB

scholarly journals TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

2018 ◽  
Vol 116 (1) ◽  
pp. 211-216 ◽  
Author(s):  
Bochra Zidi ◽  
Christelle Vincent-Fabert ◽  
Laurent Pouyet ◽  
Marion Seillier ◽  
Amelle Vandevelde ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Immune Cell ◽  
B Lymphopoiesis ◽  
Hematopoietic Stem ◽  
Chronic Oxidative Stress ◽  
The Impact ◽  
Deficient Mice

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.

scholarly journals Introduction: Inequality in Education – Innovation in Methods, with reflections by Dr Nicola Ingram and Professor Melanie Nind

2015 ◽  
Vol 2 (2) ◽  
pp. 224-233
Author(s):  
Carli Ria Rowell ◽  
Siobhan Dytham ◽  
Nicola Ingram ◽  
Melanie Nind ◽  
Carli Ria Rowell ◽  
...  
Keyword(s):  
Research Funding ◽  
Future Prospect ◽  
Inequality In Education ◽  
Education Innovation ◽  
The Uk ◽  
The University ◽  
The Impact

Against a backdrop of metamorphosis in the UK educational landscape and the increased focus on ‘innovation’ in research funding and postgraduate programmes, a conference entitled ‘Inequality in Education – Innovation in Methods’ (IEIM) was held at the University of Warwick in November 2014 to offer space to reflect on ‘inequality in education’ as a field of research and the impact, and future prospect for ‘innovation in method’ in this field. This article introduces this featured section, including reflections from Dr Nicola Ingram and Professor Melanie Nind, who both delivered keynote addresses at the conference.

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