scholarly journals Comparative analysis of Mycobacterium tuberculosis-specific antigens and T-cell mitogen-stimulated interferon gamma production in hemodialysis patients and healthy individuals

2020 ◽  
Author(s):  
Heechul Park ◽  
Ye Na Kim ◽  
Sung-Bae Park ◽  
Junseong Kim ◽  
Jaewon Lim ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Cell Function ◽  
Specific Antigen ◽  
Hemodialysis Patients ◽  
Healthy Individuals ◽  
T Cell Function ◽  
Study Results ◽  
Ifn Γ ◽  
Cell Mitogen

Abstract Background The incidence of Tuberculosis (TB) is higher in patients undergoing chronic hemodialysis than in the general population; further, both the incidence and development of active TB from latent TB infection (LTBI) are considerably higher in patients undergoing hemodialysis than in any other group. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay is one of the most commonly used interferon gamma (IFN-γ) release assays (IGRAs) currently. We aim to know T-cell function of hemodialysis patients and the possible QFT false negatives. Methods In order to analyze the MTB-specific antigen-stimulated IFN-γ release in patients on hemodialysis, the QFT-GIT test was used in this study. A total of 84 hemodialysis patients and 52 healthy subjects were enrolled from Kosin University Gospel Hospital and Catholic University of Pusan, Busan, Republic of Korea; their whole blood samples were collected and used for the present study. Results The positivity results of the IGRAs in hemodialysis patients and normal subjects were 34/84 (40.4%) and 4/52 (7.6%), respectively. The mean value of MTB-specific antigen-stimulated IFN-γ in hemodialysis patients with LTBI and non-LTBI status in hemodialysis patients, healthy individuals were 1.85 IU/mL (4.44ng/mL) and 0.028 IU/mL (0.067 ng/mL) and 0.255 IU/mL (0.612 ng/mL) respectively. In addition, Of the 34 LTBI status in hemodialysis patients, 14 (41.2%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 20 (58.8%) had 10 or more T-cell mitogen-stimulated IFN-γ. Moreover, Of the 49 non-LTBI status in hemodialysis patients, 19 (38.8%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 30 (61.2%) showed T-cell mitogen-stimulated IFN-γ levels of 10 or more. On the other hand, there was no low level of T-cell mitogen-stimulated IFN-γ in the healthy individuals. Conclusion This reveals that T-cell function in hemodialysis patients was reduced as compared to the healthy individuals. Therefore, the cut-off value should be adjusted for the active TB high-risk group when using IGRA tests. The clinical manifestations of TB in patients on hemodialysis are quite non-specific, making timely diagnosis difficult, and delaying the initiation of curative treatment, delay being a major determinant of outcome.

scholarly journals Comparative Analysis of Mycobacterium Tuberculosis-Specific Antigens and T-Cell Mitogen-Stimulated Interferon Gamma Production in Hemodialysis Patients and Healthy Individuals

2020 ◽  
Author(s):  
Heechul Park ◽  
Ye Na Kim ◽  
Sung-Bae Park ◽  
Junseong Kim ◽  
Jaewon Lim ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Cell Function ◽  
Specific Antigen ◽  
Clinical Manifestations ◽  
Hemodialysis Patients ◽  
Healthy Individuals ◽  
T Cell Function ◽  
Ifn Γ ◽  
Cell Mitogen

Abstract Background: The incidence of Tuberculosis (TB) is higher in patients undergoing chronic hemodialysis than in the general population; further, both the incidence and development of active TB from latent TB infection (LTBI) are considerably higher in patients undergoing hemodialysis than in any other group. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay is one of the most commonly used interferon gamma (IFN-γ) release assays (IGRAs) currently. We aim to know T-cell function of hemodialysis patients and the possible QFT false negatives.Methods: In order to analyze the MTB-specific antigen-stimulated IFN-γ release in patients on hemodialysis, the QFT-GIT test was used in this study. A total of 84 hemodialysis patients and 52 healthy subjects were enrolled from Kosin University Gospel Hospital and Catholic University of Pusan, Busan, Republic of Korea; their whole blood samples were collected and used for the present study.Results: The positivity results of the IGRAs in hemodialysis patients and normal subjects were 34/84 (40.4%) and 4/52 (7.6%), respectively. The median value of MTB-specific antigen-stimulated IFN-γ in hemodialysis patients with LTBI and non-LTBI status in hemodialysis patients, healthy individuals were 1.85 IU/mL (4.44ng/mL) and 0.028 IU/mL (0.067 ng/mL) and 0.255 IU/mL (0.612 ng/mL) respectively. In addition, Of the 34 LTBI status in hemodialysis patients, 14 (41.2%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 20 (58.8%) had 10 or more T-cell mitogen-stimulated IFN-γ. Moreover, Of the 49 non-LTBI status in hemodialysis patients, 19 (38.8%) and 30 (61.2%) respectively. On the other hand, there was no low level of T-cell mitogen-stimulated IFN-γ in the healthy individuals.Conclusion: This reveals that T-cell function in hemodialysis patients was reduced as compared to the healthy individuals. Therefore, the cut-off value should be adjusted for the active TB high-risk group when using IGRA tests. The clinical manifestations of TB in patients on hemodialysis are quite non-specific, making timely diagnosis difficult, and delaying the initiation of curative treatment, delay being a major determinant of outcome.

scholarly journals Investigation of IL-2 and IFN-γ to EBV Peptides in Stimulated Whole Blood among Multiple Sclerosis Patients and Healthy Individuals

Intervirology ◽  
2021 ◽  
pp. 1-6
Author(s):  
Nastaran Rafiee ◽  
Mehrdad Ravanshad ◽  
Bahador Asadi ◽  
Roya Kianfar ◽  
Ali Maleki
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
B Lymphocytes ◽  
Whole Blood ◽  
Cell Function ◽  
Mrna Level ◽  
Healthy Individuals ◽  
T Cell Function ◽  
Ifn Γ ◽  
Multiple Sclerosis Patients

<b><i>Introduction:</i></b> Epstein-Barr virus (EBV), a double-stranded DNA virus, has 2 phases of lytic and latent infection in host cells. After infecting B lymphocytes, EBV becomes persistent in these cells. In healthy individuals, T lymphocytes play a key role in killing EBV-infected B cells. Statistical studies have shown that symptomatic EBV infection increases the risk of MS. <b><i>Methods:</i></b> This study intended to measure the immune system’s response against the different components of EBV, focusing particularly on T lymphocytes’ reaction. Consequently, the mRNA level of IL-2 and IFN-γ, liable for impressing autoimmune diseases and as indicators of T-cell function, was compared in EBNA1- and BRLF1-treated whole blood (WB) cultures of 10 healthy individuals and 10 MS patients using real-time RT-PCR. <b><i>Results:</i></b> The analysis of the results demonstrated a significant increased level of IL-2 in MS patients than healthy subjects after exposure to both peptides. Also, the mRNA level of IFN-γ increased in MS patients in EBNA1-treated WB culture. <b><i>Conclusion:</i></b> According to the study’s results, EBV peptides can reactivate immune cells, especially T lymphocytes, and may indirectly induce inflammation and develop MS; however, it seems that long-time exposure to these peptides has reducing effect on T-cell function and faces the control of infected B lymphocytes with difficulties.

scholarly journals Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

2016 ◽  
Vol 64 (12) ◽  
pp. 753-767 ◽  
Author(s):  
Scott M. Tanner ◽  
Joseph G. Daft ◽  
Stephanie A. Hill ◽  
Colin A. Martin ◽  
Robin G. Lorenz
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cell Function ◽  
Interleukin 17 ◽  
Intestinal Tumor ◽  
Double Positive ◽  
Tumor Immunosurveillance ◽  
T Cell Function ◽  
Ifn Γ ◽  
Cell Balance

The adenomatous polyposis coli ( APC) gene is a known tumor suppressor gene, and mice with mutations in Apc (ApcMin/+) spontaneously form multiple intestinal neoplasms. In this model of human colorectal cancer (CRC), it has been reported that CD4+ T-cell-derived interleukin 17 (IL-17) promotes intestinal tumor development, but it is not known if the Apc mutation actually directly alters T-cell function and subsequently tumor immunosurveillance. To investigate the ApcMin/+ mutation on T-cell function, flow cytometric, histochemical, and immunofluorescent studies on both wild-type (Apc+/+) and ApcMin/+ mice were performed. We identified decreased levels of interferon gamma (IFN-γ+)IL-17+ double-positive CD4+ cells in the mesenteric lymph nodes and Peyer’s patches of ApcMin/+ mice. In addition, altered levels of CD8+ cells, and changes in CD8+ production of IFN-γ and granzyme B were observed. These T-cell alterations did modify tumor immunosurveillance, as the adoptive transfer of splenocytes from ApcMin/+ animals into a chemically induced CRC model resulted in the inability to prevent epithelial dysplasia. These results suggest an altered T-cell balance in ApcMin/+ mice may disrupt intestinal homeostasis, consequently limiting intestinal tumor immunosurveillance.

scholarly journals The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

2007 ◽  
Vol 81 (6) ◽  
pp. 2940-2949 ◽  
Author(s):  
Adam J. Gehring ◽  
Dianxing Sun ◽  
Patrick T. F. Kennedy ◽  
Esther Nolte-'t Hoen ◽  
Seng Gee Lim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Antigen ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Function ◽  
Tnf Α ◽  
Antiviral Function ◽  
Ifn Γ

ABSTRACT CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-γ and TNF-α production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.

Effect of pazopanib on myeloid-derived suppressor cells and T-cell function in patients with metastatic renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 455-455
Author(s):  
Kiranpreet K. Khurana ◽  
Pat A. Rayman ◽  
Paul Elson ◽  
Brian I. Rini ◽  
James Finke
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
T Cell Function ◽  
Pre Treatment ◽  
Over Time

455 Background: Tyrosine kinase inhibitors have been shown to have an effect on T cell function. Sunitinib decreases immunosuppression in patients with metastatic renal cell carcinoma (mRCC) as seen by a reduction in myeloid derived suppressor cells (MDSC) that inhibit T cell function. The effect of pazopanib on immune function is unknown. Methods: Peripheral blood mononuclear cells from 21 patients with mRCC treated with pazopanib were thawed for cycle 1 day 1, cycle 1 day 28, cycle 2 day 28, and cycle 4 day 28. Total MDSC and neutrophilic, monocytic, and lineage-negative MDSC subsets were measured by flow cytometry. T cell response was measured by interferon-gamma production after in vitro stimulation by anti-CD3/anti-CD28 beads. Pre-treatment cycle 1 day 1 levels were compared to cycle 4 day 28. Results: In mRCC patients, MDSCs comprise 4.7 % (median, range 1.7-32.9 %) of the peripheral blood mononuclear cells pre-treatment. Neutrophilic MDSC subset is the most prevalent at 2.0 % (median, range 0.3-30.4 %). Monocytic MDSCs comprise 1.5 % (median, range 0.4-5.3 %), and lineage-negative MDSCs comprise only 0.15 % (median, range 0.01-1.03 %). We found that pazopanib does not significantly decrease the percentage of MDSCs (total or subpopulations) over time with the exception of a modest decrease in the lineage-negative MDSC subset (p = 0.08). In terms of T cell function, pre-treatment level of CD3+ interferon-gamma was found to be 10.6 % (median, range 1.3-22.3 %). In contrast, pazopanib significantly increased CD3+ interferon-gamma level over time to 18.1 % (median, range 3.0-25.0 %), p = 0.03. Conclusions: Our study shows that pazopanib does not significantly reduce MDSC levels in patients with mRCC. However, pazopanib improves T cell function over time, as seen by a significant increase in CD3+ interferon-gamma production.

Evidence of Impaired T Cell Function in Hemodialysis Patients: Potential Role for Secondary Hyperparathyroidism

1990 ◽  
Vol 10 (6) ◽  
pp. 495-501 ◽  
Author(s):  
Jadwiga M. Alexiewicz ◽  
Zbigniew Gaciong ◽  
Marian Klinger ◽  
Mariana Linker-Israeli ◽  
Thomas O. Pitts ◽  
...  
Keyword(s):  
T Cell ◽  
Secondary Hyperparathyroidism ◽  
Potential Role ◽  
Cell Function ◽  
Hemodialysis Patients ◽  
T Cell Function

scholarly journals Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8014-8014 ◽  
Author(s):  
T. F. Gajewski ◽  
D. Niedzwiecki ◽  
J. Johnson ◽  
G. Linette ◽  
C. Bucher ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cell Function ◽  
Immunosuppressive Agents ◽  
Single Agent ◽  
Clinical Activity ◽  
Combination Therapies ◽  
T Cell Function ◽  
Ifn Γ

8014 Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. Methods: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. Results: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85–98%) in tumor tissue. T cell production of IFN-γ was also suppressed. Conclusions: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed. [Table: see text]

PD-1 Protects Liver Damage by Suppressing IFN-γ Expression in T Cells in Infants and Neonatal Mice

2021 ◽  
Author(s):  
Xuangjie Guo ◽  
Yiping Xu ◽  
Wei Luo ◽  
Li Cai ◽  
Ping Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Protective Role ◽  
Control Subjects ◽  
T Cell Function ◽  
Ifn Γ ◽  
And Control

Abstract Background: Biliary atresia (BA) is a severe cholangiopathy resulting from virus-induced and immune-mediated injury of the biliary system. IFN-g, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death 1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods: Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results: PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver. Blockade of PD-1 increased IFN-g expression in CD4+ T and CD8+ T cells, suppressed bilirubin production and exacerbated liver immunopathology.Conclusions: PD-1 plays a protective role in infants with BA by suppressing IFN-g production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

scholarly journals Programmed cell death protein-1 (PD-1) protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuangjie Guo ◽  
Yiping Xu ◽  
Wei Luo ◽  
Rongli Fang ◽  
Li Cai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Protective Role ◽  
Control Subjects ◽  
T Cell Function ◽  
Ifn Γ ◽  
And Control

Abstract Background Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = − 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = − 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 μmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. Conclusions PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

T-Cell Function in Patients with B-Cell Chronic Lymphocytic Leukemia (B-CLL) Following Alemtuzumab (Campath®) or Fludarabine Treatment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2513-2513
Author(s):  
Shahryar Kiaii ◽  
Fariba Mozaffari ◽  
Jeanette Lundin ◽  
Reza Rezvany ◽  
Aniruddha Chudhury ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Proliferative Response ◽  
Cell Function ◽  
T Cell Subsets ◽  
Control Group ◽  
Antitumor Effects ◽  
T Cell Function ◽  
Increased Risk ◽  
Ifn Γ

Abstract Fludarabine and alemtuzumab (humanized anti-CD52 antibody, Campath®) are both used as routine therapy for patients with B-CLL. Fludarabine and in particular alemtuzumab, in addition to their antitumor effects, induce long-lasting suppression of T-cell numbers in blood. T-cell suppression, in combination with advanced disease, may result in an increased risk of opportunistic and other infections. In addition to a decrease in circulating T cells, functional defects in T cells have been described following alemtuzumab therapy for non-malignant disorders; however, only a limited amount of information exists about the effect of alemtuzumab on T-cell function in patients with B-CLL. The aim of the present study was to characterize in detail various aspects of T-cell function in patients with B-CLL who were in stable unmaintained PR or CR following fludarabine (n = 9) and alemtuzumab (n = 10) treatment as well as in age-matched healthy control donors (n = 10). CD4 and CD8 T-cell subsets of freshly obtained peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry to measure the expression of TCR-CD3 ζ chain, p56Lck, p59Fyn, ZAP-70, and PI3 Kinase as well as intracellular production of IFN-γ and IL-4. Additional analyses were performed to measure the proliferative response capability to a recall antigen (PPD) in alemtuzumab-treated patients and (as a control) indolent, untreated B-CLL patients (n = 11). The expression of IFN-γ and IL-4 (measured as mean fluorescence intensity [MFI]), but not the total number of positive cells, was significantly higher in CD4 and CD8 T cells for both CLL groups compared to healthy donors with the highest expression observed in alemtuzumab-treated patients. The total number of T cells that expressed the five signaling molecules was significantly lower in treated patients versus control donors; however, there were no differences between fludarabine- and alemtuzumab-treated patients. MFI analysis showed a significant increase in the TCR-CD3 ζ chain in fludarabine-treated patients compared to control donors; however, MFI analysis revealed no other significant differences between control group patients and fludarabine- and alemtuzumab-treated patients. Moreover, the proliferative response to PPD was not significantly different in alemtuzumab-treated patients and indolent CLL patients. In conclusion, these results suggest that the intrinsic signal transduction machinery in T cells is relatively well-preserved, such that T cells remain functionally intact following fludarabine or alemtuzumab therapy despite a marked reduction in their numbers. These results provide a better understanding of the immune suppression induced by alemtuzumab and fludarabine therapy in B-CLL patients.

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