Blood CD3-(CD56 or 16)+ natural killer cell distributions are heterogeneous in healthy adults and suppressed by azathioprine in patients with ANCA-associated vasculitides

Abstract Background Cytotoxic Natural Killer (NK) cells are increasingly recognized as a powerful tool to induce targeted cell death in cancer and autoimmune diseases. Still, basic blood NK cell parameters are poorly defined. The aims of this study were 1) to establish reference values of NK cell counts and percentages in healthy adults; 2) to describe these parameters in the prototype autoimmune disease group ANCA-associated vasculitis (AAV); and 3) to investigate whether NK cell counts and percentages may be used as activity biomarkers in the care of AAV patients, as suggested by a preceding study. Methods CD3-(CD56 or 16)+ NK cell counts and percentages were determined in 120 healthy adults. Lymphocyte subset and clinical data from two German vasculitis centers were analyzed retrospectively (in total 407 measurements, including 201/49/157 measurements from 64/16/39 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively). Results CD3-(CD56 or 16)+ NK cell counts and percentages in healthy adults were highly variable, not Gaussian distributed and independent of age and sex. NK cell percentages ranged from 1.9 to 37.9% of lymphocytes, and were significantly more dispersed in AAV (0.3 to 57.6%), while the median percentage was not different between AAV and healthy donors. In contrast, median NK cell counts were significantly lower in AAV compared to healthy donors. Sub-group analyses revealed that NK cell counts were low independent of AAV entity and disease activity. Azathioprine therapy was associated with significantly lower NK cell counts and percentages compared to non-azathioprine therapies. In 13.6% of azathioprine-treated patients, percentages were </= 1% which may be interpreted as temporary NK cell deficiency. NK cell counts and percentages could not separate active from inactive AAV. Conclusions NK cell counts and percentages in blood are heterogeneous and can presently not be recommended as biomarker in clinical care of AAV patients. Azathioprine treatment was associated with significantly low NK cells. These findings may be relevant for the development of drugs that aim at exploiting NK cell cytotoxicity and may help to identify patients at risk to develop malignant or infectious co-morbidities.

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CD3-(CD56 or 16)+ natural killer cell distribution in blood from healthy adults and patients with ANCA-associated vasculitis

10.21203/rs.3.rs-54782/v1 ◽

2020 ◽

Author(s):

Wolfgang Merkt ◽

Ulrich Salzer ◽

Jens Thiel ◽

Ilona Jandova ◽

Raoul Bergner ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Granulomatosis With Polyangiitis ◽

Nk Cell ◽

Inflammatory Diseases ◽

Clinical Care ◽

Healthy Adults ◽

Eosinophilic Granulomatosis With Polyangiitis ◽

Cell Counts ◽

Anca Associated Vasculitis

Abstract BackgroundCytotoxic Natural Killer (NK) cells are an important target of new drugs entering the clinics, including checkpoint inhibitors and cell-depleting therapeutic antibodies. Still, basic blood NK cell parameters are poorly defined in healthy adults and in chronic inflammatory diseases like ANCA-associated vasculitis (AAV) which may alter the distribution of lymphocytes. The aims of this study were 1) to establish reference values of NK cell counts and percentages in healthy adults; 2) to describe these parameters in AAV; and 3) to investigate whether NK cell counts and percentages may be used as activity biomarker in the care of AAV patients, as suggested by a preceding study.MethodsCD3-(CD56 or 16)+ NK cell counts and percentages were determined in 120 healthy adults. Lymphocyte subset data from two German vasculitis centers were retrospectively analyzed (in total 407 measurements, including 201/49/157 measurements from 64/16/39 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively).ResultsCD3-(CD56 or 16)+ NK cell counts and percentages in healthy adults were highly variable, not Gaussian distributed and independent of age and sex. NK cell percentages ranged from 1.9 to 37.9% of lymphocytes, and were significantly more dispersed in AAV (0.3 to 57.6%). We further found that NK cell counts and percentages were different between AAV entities. However, during active disease, NK cell counts were consistently low in each AAV entity compared to healthy donors. NK cells were especially low in inactive EGPA. In 18% of EGPA patients we observed percentages of 1% or below which may be interpreted as temporary NK cell deficiency. Findings on differences between active and inactive GPA were discrepant between vasculitis centers.ConclusionsNK cell counts and percentages in blood are highly variable. This variability is further enhanced in systemic inflammatory diseases, and includes patients with temporary NK cell deficiency, in particular in EGPA. NK cell counts and percentages can presently not be recommended as biomarker in clinical care of AAV patients.

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Aberrant anti-viral response of natural killer cells in severe asthma

European Respiratory Journal ◽

10.1183/13993003.02422-2018 ◽

2020 ◽

Vol 55 (5) ◽

pp. 1802422

Author(s):

Justine Devulder ◽

Cécile Chenivesse ◽

Valérie Ledroit ◽

Stéphanie Fry ◽

Pierre-Emmanuel Lobert ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Severe Asthma ◽

Cell Activation ◽

Mononuclear Cells ◽

Nk Cell ◽

Peripheral Blood Mononuclear ◽

Healthy Donors ◽

Asthma Patients ◽

Ifn Γ

Rhinovirus infections are the main cause of asthma exacerbations. As natural killer (NK) cells are important actors of the antiviral innate response, we aimed at evaluating the functions of NK cells from severe asthma patients in response to rhinovirus-like molecules or rhinoviruses.Peripheral blood mononuclear cells from patients with severe asthma and healthy donors were stimulated with pathogen-like molecules or with the rhinoviruses (RV)-A9 and RV-2. NK cell activation, degranulation and interferon (IFN)-γ expression were analysed.NK cells from severe asthma patients were less cytotoxic than those from healthy donors in response to toll-like receptor (TLR)3, TLR7/8 or RV-A9 but not in response to RV-2 stimulation. Furthermore, when cultured with interleukin (IL)-12+IL-15, cytokines which are produced during viral infections, NK cells from patients with severe asthma were less cytotoxic and expressed less IFN-γ than NK cells from healthy donors. NK cells from severe asthmatics exhibited an exhausted phenotype, with an increased expression of the checkpoint molecule Tim-3.Together, our findings indicate that the activation of NK cells from patients with severe asthma may be insufficient during some but not all respiratory infections. The exhausted phenotype may participate in NK cell impairment and aggravation of viral-induced asthma exacerbation in these patients.

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Long Lasting Alteration of Natural Killer Cells Post-Chemotherapy in Elderly Patients with Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v114.22.1653.1653 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1653-1653

Author(s):

Daniel Olive ◽

Nicolas Anfossi ◽

Pascale Andre ◽

Jerome Rey ◽

Florence Orlanducci ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

Elderly Patients ◽

Nk Cells ◽

Natural Killer ◽

Cd8 T Cells ◽

Nk Cell ◽

Time Points ◽

Early Stages ◽

Cell Counts

Abstract Abstract 1653 Poster Board I-679 Background The immune system is involved in AML control and Natural Killer (NK) cells are among the most promising effectors. The therapeutic potential of NK cells has been revealed by the Killer Immunoglobulin Receptor (KIR) mismatch allogeneic transplant model where the anti-leukemic effect of the graft, is due to unleashed NK cells towards AML blasts, as suggested by enhanced in vitro lytic activity of KIR-HLA mismatched donor NK cells against recipient blasts (Miller et al. 2005; Ruggeri et al. 2002). Receptors involved in the function of NK cells against AML blasts have been identified (Pende et al., 2005). Some of these receptors are altered in AML patients at diagnosis and might be involved in the immune escape of AML blasts (Costello et al., 2002). However, the status of NK cells during early stages of patient's chemotherapy (CT) treatment is unknown. The present study monitored status of NK cells during early stages following patient's remission after CT that may be critical for their long lasting clinical response, and results might provide new targets for immunotherapy. Methods We enrolled 20 elderly patients (60 to 80 years old) with non promyelocytic AML in first CR following induction and pre-consolidation CT with normal renal and hepatic functions. Patient peripheral NK, gd T and CD8 T cells were analyzed before consolidation CT and every other week after treatment for 8 weeks. 6-colors flow cytometry was performed to investigate the expression of MHC receptors (CD158a, b, e, i, CD85j and NKG2A), activating receptors (NKp30, NKp46, NKG2D, CD16, DNAM-1, 2B4) as well as their differentiation status (perforin and granzyme expression). Their function, as determined by cytotoxicity (51Cr release and CD107 expression) and cytokine production (intracellular staining of IFN-g), was analyzed using purified NK cells stimulated by K562, or in redirected assays using NKp30, NKp46 and CD16 mAbs. Results NK cell counts were depressed away from the induction and pre-consolidation CT as compared to NK cell counts of age-matched controls (ctl) (95±107 NK/μL vs 229±91 NK/μL respectively); they were further depressed during the first 2 weeks post-consolidation CT (55±57 NK/μL), but were back to pre-consolidation CT level at 4 weeks (105±102 NK/μL). In contrast, CD8 T cells and gd T cells counts were normal even at early times post-CT. Expression of 2B4 was depressed at all time points. In contrast, NKp30 expression was lower at diagnosis and close to ctl level post-consolidation CT (p=0.0003) and NKp46 expression increased after CT (p<0.0001). Sizes of NK cell subsets expressing CD158a or CD158b in patients post-induction and consolidation CT were smaller than those of ctl (% CD158a+: p=0.003; % CD158b+: p=0.014). In contrast the NKG2A or CD85j positive NK cell subsets were either unchanged or slightly increased respectively at all time points (p=0.0015 for CD85j+). Moreover, sizes of perforin or granzyme positive NK cell subsets were increased in treated AML patients (% Granzyme+: p= 0.0125 and % Perforin+: p=0.0268). In addition, we observed an important heterogeneity in the expression of the surface receptors among patients that is currently analyzed with respect to the duration of the CR. Finally, NK cell cytoxicity was comparable at all time points to the one of age-matched ctl. In contrast, IFN-g secretion was decreased, at all time points, against K562 or in redirected assays using CD16 mAb and almost abolished using redirected assay with NKp30 mAb. Conclusions This study demonstrates that in elderly AML patients in CR after CT (1) several alterations are detected at all time points, (2) NK cell number is lower and (3) IFN-g secretion is impaired. However NK cytotoxic function is comparable to age-matched controls. The likely basis of the complex pattern of modifications might rely on an interplay between the direct and indirect effects of chemotherapy, activation of immune system, NK cell differentiation and its interaction with AML blasts. Altogether this study indicates that new immunotherapeutic approaches might be used to increase NK cell numbers and functions (cytotoxicity and IFN-g secretion) at early times post-CT in elderly patients with AML. Disclosures Romagne: Innate Pharma: Employment.

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Natural Killer Cells Recovery After Consolidation Chemotherapy in Elderly Patients with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v118.21.2189.2189 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2189-2189 ◽

Cited By ~ 3

Author(s):

Jerome Rey ◽

Nicolas Anfossi ◽

Pascale Andre ◽

Jean-Marie Boher ◽

Florence Orlanducci ◽

...

Keyword(s):

Elderly Patients ◽

Nk Cells ◽

Natural Killer ◽

Immune Escape ◽

Nk Cell ◽

Residual Disease ◽

Leukemic Cells ◽

Consolidation Chemotherapy ◽

Cell Counts

Abstract Abstract 2189 Background: Human Natural Killer (NK) cells are able to kill abnormal cells while preserving normal cells. Accumulating clinical and experimental data point toward a key role of these cells in the control and clearance of most if not all hematologic malignancies. Recent insights into NK have stimulated studies of innate immunity in haematological malignancies, as the role of NK cells in allogeneic transplantation. Better knowledge of the deficiencies of these effector cells can allow elaborating new protocols of immunotherapy in order to directly enhance their capacity to eliminate tumor cells. Hence, the mechanisms of recognition and killing of leukemic cells and their role in vivo have only been investigated very recently. Even though lysis of leukemic cells or leukemic cell lines by NK cells has been described in vitro, mechanisms underlying the interaction and destruction of these cells are not clearly defined. Some of these receptors are altered in AML patients at diagnosis and might be involved in the immune escape of AML blasts. However, the recovery of NK cells during consolidation chemotherapy treatment has not been studied. The present study monitored status of NK cells following patient's remission after chemotherapy in order to provide new targets for immunotherapy. Methods: We enrolled 29 elderly patients (mean: 70-years old) with non promyelocytic AML in first CR following induction and pre-consolidation chemotherapy. Patient peripheral NK cells were analyzed at diagnosis, before consolidation chemotherapy and every two weeks after treatment for 8 weeks. 6-colors flow cytometry was performed to investigate the expression of MHC receptors (CD158a, b, e, i, CD85j and NKG2A), activating receptors (NKp30, NKp46, NKG2D, CD16, DNAM-1, 2B4) as well as their differentiation status (perforin and granzyme expression). Their function, as determined by cytotoxicity (51Cr release and CD107 expression) and cytokine production (intracellular staining of IFN-g), was analyzed using purified NK cells stimulated by K562, or in redirected assays using NKp30, NKp46 and CD16 mAbs. The recovery of these receptors was then correlated with PFS and OS. Results: NK cell counts were depressed after induction and pre-consolidation chemotherapy as compared to NK cell counts of age-matched controls; they were further depressed during the first 2 weeks post-consolidation chemotherapy, but were back to pre-consolidation chemotherapy level at 4 weeks. NKp30 and NKp46 expression was lower at diagnosis as compared to controls but their levels restored progressively after induction and consolidation chemotherapy. NKG2D expression were depressed at pre-consolidation but increased after consolidation chemotherapy. For inhibitory receptors, CD158a or CD158b expressions were depressed at diagnosis, at post-induction and consolidation chemotherapy. In contrast, the NKG2A positive NK cell subsets increased progressively after consolidation chemotherapy. Moreover, sizes of perforin or granzyme positive NK cell subsets were increased in treated AML patients. K562 cytotoxicity was depressed after induction chemotherapy but increased after consolidation chemotherapy. In contrast, IFN-g secretion was decreased, at all time points. Finally, we try to correlate the recovery of these different receptors with OS and PFS. NKp30 and NKG2D recovery seems to be correlated with better PFS and OS. Conclusions: This study confirms that NK cells from AML patients displayed different phenotype and functional abnormalities at diagnosis. Chemotherapy seems to have different impact on the recovery of inhibitory or activatory NK receptors. The predominant data is that NK cells recovered rapidly after consolidation chemotherapy and seems to be more operational at that time. Immunotherapy of NK cells must be probably developed post consolidation chemotherapy when NK cells are ready and residual disease low. Antibodies to stimulate NK cells are actually evaluated in this setting. Disclosures: Anfossi: Innate Pharma: Employment. Andre:Innate Pharma: Employment. Breso:Innate Pharma: Employment. Perri:Innate Pharma: Employment. Romagne:Innate Pharma: Employment.

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Natural Killer Cell Function Is Well Preserved in Asymptomatic Human Immunodeficiency Virus Type 2 (HIV-2) Infection but Similar to That of HIV-1 Infection When CD4 T-Cell Counts Fall

Journal of Virology ◽

10.1128/jvi.80.5.2529-2538.2006 ◽

2006 ◽

Vol 80 (5) ◽

pp. 2529-2538 ◽

Cited By ~ 27

Author(s):

Samuel Victor Nuvor ◽

Marianne van der Sande ◽

Sarah Rowland-Jones ◽

Hilton Whittle ◽

Assan Jaye

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Human Immunodeficiency Virus Type ◽

Nk Cell ◽

Cell Counts ◽

Immunodeficiency Virus ◽

Ifn Γ ◽

Hiv 1

ABSTRACT Natural killer (NK) cells are potent effectors of natural immunity and their activity prevents human immunodeficiency virus type 1 (HIV-1) viral entry and viral replication. We sought to determine whether NK immune responses are associated with different clinical course of HIV-1 and HIV-2 infections. A cross-sectional analysis of NK cell responses was undertaken in 30 HIV-1 and 30 HIV-2 subjects in each of three categories of CD4+-T-cell counts (>500, 200 to 500, and <200 cells/μl) and in 50 HIV-uninfected control subjects. Lytic activity and gamma interferon (IFN-γ) secretion were measured by chromium release and enzyme-linked immunospot assays, respectively. Flow cytometry was used to assess intracellular cytokines and chemokines. Levels of NK cytotoxicity were significantly higher in HIV-2 than in HIV-1 infections in subjects with high CD4+-T-cell counts and were similar to that of the healthy controls. In these HIV-2 subjects, cytolytic activity was positively correlated to NK cell count and inversely related to plasma viremia. Levels of intracellular MIP-1β, RANTES, tumor necrosis factor alpha, and IFN-γ produced by NK CD56bright cells were significantly higher in HIV-2- than HIV-1-infected subjects with high CD4+-T-cell counts but fell to similar levels as CD4 counts dropped. The data suggest efficient cytolytic and chemokine-suppressive activity of NK cells early in HIV-2 infection, which is associated with high CD4+ T-cell counts. Enhancement of these functions may be important in immune-based therapy to control HIV disease.

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Fusion Proteins of Ligands for NKG2D and CD20-Directed ScFvs Sensitize Lymphomas for NK Cell-Mediated Lysis

Blood ◽

10.1182/blood.v116.21.2843.2843 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2843-2843

Author(s):

Christian Kellner ◽

Daniela Hallack ◽

Pia Glorius ◽

Matthias Staudinger ◽

Sahar Mohseni Nodehi ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Mhc Class I ◽

Fusion Proteins ◽

Nk Cell ◽

Effector Cells ◽

Healthy Donors

Abstract Abstract 2843 Natural killer group 2 member D (NKG2D) is an important activating receptor controlling cytotoxicity of natural killer (NK) cells and T cells and plays an important role in immune surveillance against tumors. For redirecting NK cells to B-lymphoid tumor cells two recombinant bifunctional antibody-based fusion proteins were designed in order to coat malignant cells with ligands for NKG2D and attract NK cells. Therefore, a human CD20-directed single-chain fragment variable (scFv) was fused to NKG2D-specific ligands, either MHC class I chain-related protein A (MICA) or unique long 16-binding protein 2 (ULBP2). These two fully human fusion proteins, designated MICA:CD20 and ULBP2:CD20, respectively, were expressed in eukaryotic cells and purified to homogeneity. Size exclusion chromatography revealed that both purified proteins predominantly formed monomers. MICA:CD20 and ULBP2:CD20 specifically and simultaneously bound to CD20 and NKG2D and efficiently mediated lysis of lymphoma cell lines with mononuclear cells from healthy donors as effector cells. Analysis of the activation status of NKG2D-positive T cells and NK cells revealed that MICA:CD20 and ULBP2:CD20 activated resting NK cells, but not T cells, indicating that NK cells were the relevant effector cell population for the two molecules. In cytotoxicity assays using human NK cells from healthy donors, both agents sensitized lymphoma cell lines as well as fresh tumor cells for NK cell-mediated lysis. MICA:CD20 and ULBP2:CD20 induced lysis at low nanomolar concentrations with half maximum effective concentrations between 1 and 4 nM depending on target cells. Interestingly, ULBP2:CD20 exhibited a higher cytolytic potential than MICA:CD20 in terms of maximum lysis. Importantly, MICA:CD20 and ULBP2:CD20 induced lysis of 13/13 tested primary tumor cell samples from patients with different B cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and marginal zone lymphoma. Interestingly, cell surface expression of endogenous MICA and ULBP2 was low or not detectable on fresh tumor cells. In addition, ULBP2:CD20 was also capable of inducing lysis of tumor cells in cytotoxicity experiments using autologous patient-derived NK cells as effector cells, indicating that the triggering signal was sufficient to overcome inhibition by interactions between killer cell immunoglobulin-like receptors and MHC class I molecules. Moreover, both MICA:CD20 and ULBP2:CD20 synergistically enhanced antibody-dependent cellular cytotoxicity (ADCC) by the monoclonal antibody daratumumab directed against CD38 which is co-expressed together with CD20 on certain B cell lymphomas. This approach of simultaneously triggering ADCC and natural cytotoxicity by these bifunctional fusion proteins may represent a promising strategy to achieve stronger NK cell-mediated antitumor responses. Disclosures: de Weers: Genmab : Employment. van De Winkel:Genmab: Employment. Parren:Genmab: Employment.

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Indomethacin inhibits circulating PGE2 and reverses postexercise suppression of natural killer cell activity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.5.r1496 ◽

1999 ◽

Vol 276 (5) ◽

pp. R1496-R1505

Author(s):

Shawn G. Rhind ◽

Greg A. Gannon ◽

Masatoshi Suzui ◽

Roy J. Shephard ◽

Pang N. Shek

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Strenuous Exercise ◽

Double Blind ◽

Cell Counts ◽

Ergometer Exercise

Natural killer (NK) cells are important in combating viral infections and cancer. NK cytolytic activity (NKCA) is often depressed during recovery from strenuous exercise. Lymphocyte subset redistribution and/or inhibition of NK cells via soluble mediators, such as prostaglandin (PG) E2 and cortisol, are suggested as mechanisms. Ten untrained (peak O2 consumption = 44.0 ± 3.5 ml ⋅ kg−1 ⋅ min−1) men completed at 2-wk intervals a resting control session and three randomized double-blind exercise trials after the oral administration of a placebo, the PG inhibitor indomethacin (75 mg/day for 5 days), or naltrexone (reported elsewhere). Circulating CD3−CD16+/56+NK cell counts, PGE2, cortisol, and NKCA were measured before, at 0.5-h intervals during, and at 2 and 24 h after a 2-h bout of cycle ergometer exercise (65% peak O2 consumption). During placebo and indomethacin conditions, exercise induced significant ( P < 0.0001) elevations of NKCA (>100%) and circulating NK cell counts (>350%) compared with corresponding control values. With placebo treatment, total NKCA was suppressed (28%; P < 0.05) 2 h after exercise, and a postexercise elevation (36%; P = 0.02) of circulating PGE2 was negatively correlated ( r = 0.475, P = 0.03) with K-562 tumor cell lysis. NK counts were unchanged in the postexercise period, but at this stage CD14+ monocyte numbers were elevated ( P < 0.0001). Indomethacin treatment eliminated the postexercise increase in PGE2 concentration and completely reversed the suppression of total and per CD16+56+NKCA 2 h after exercise. These data support the hypothesis that the postexercise reduction in NKCA reflects changes in circulating PGE2 rather than a differential lymphocyte redistribution.

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Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients.

Journal of Experimental Medicine ◽

10.1084/jem.175.3.789 ◽

1992 ◽

Vol 175 (3) ◽

pp. 789-796 ◽

Cited By ~ 126

Author(s):

J Chehimi ◽

S E Starr ◽

I Frank ◽

M Rengaraju ◽

S J Jackson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cytotoxic Activity ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Target Cells ◽

Cell Functions ◽

Healthy Donors ◽

Immunodeficiency Virus ◽

Stimulatory Factor

Natural killer cell stimulatory factor (NKSF), or interleukin 12 (IL-12), is a heterodimeric lymphokine produced by B cells that has multiple effects on T and NK cell functions. NKSF at concentrations as low as 0.4 pM enhances the spontaneous cytotoxic activity of peripheral blood lymphocytes (PBL) against a variety of tumor-derived target cell lines and virus-infected target cells. The combined treatment of PBL with NKSF and IL-2 results in a less than additive enhancement of cytotoxicity. NKSF enhances the cytotoxic activity of spontaneously cytotoxic CD16+CD5- NK cells and does not confer cytotoxic activity to CD16-CD5+ T cells. PBL from patients infected with human immunodeficiency virus (HIV) have significantly lower cytotoxic activity against tumor-derived target cells and virus-infected target cells than PBL from control healthy donors. Treatment of PBL from HIV-infected patients with NKSF and/or IL-2 results in an increase of NK cell cytotoxicity against both types of target cells to levels similar to or higher than those of untreated PBL from healthy donors. PBL from HIV-infected patients produce interferon gamma in response to NKSF and/or IL-2, although at levels 5- or 10-fold lower than those produced by PBL from healthy donors. The multiple biological effects of NKSF, its activity at very low molar concentrations, and its ability to synergize with other physiological stimuli suggest that NKSF/IL-12 is a lymphokine likely to have physiological importance and considerable therapeutic potential.

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Reduced levels of circulating natural killer cells in children with celiac disease

Paediatrica Indonesiana ◽

10.14238/pi60.3.2020.125-30 ◽

2020 ◽

Vol 60 (3) ◽

pp. 125-30

Author(s):

Mehmet Agin ◽

Eylem Sevinc ◽

Erkan Dogan ◽

Nergiz Sevinc

Keyword(s):

Celiac Disease ◽

Nk Cells ◽

Cell Count ◽

Natural Killer ◽

Peripheral Blood ◽

Nk Cell ◽

Absolute Number ◽

Gluten Free ◽

Cell Counts ◽

The Absolute

Background Celiac disease (CD) is an autoimmune disease characterized by malabsorption. Serologic testing for CD consists of Ig A type of antitissue transglutaminase (tTG), antiendomysium (EMA). These tests are helpful in monitoring adherence to the gluten-free diet (GFD). Natural killer (NK) cell count alterations have been reported in various diseases, such as cancer, Crohn’s disease, malnutrition, and autoimmune disorders. Objective To compare peripheral blood NK cell counts in children with celiac disease (CD) to healthy controls. The second aim was to analyze for possible correlations between NK cells (CD3-/CD16+, CD56+) and tissue transglutaminase (tTG)-IgA and tTG-IgG, as well as endomysial antibody EMA-IgA indicating gluten sensitivity. Methods Fifty children with CD were compared to 48 healthy children as controls, with similar age and sex distribution. Peripheral blood NK cell counts were measured by flow cytometry. Results The median (P25-P75) ages of the 50 celiac patients (23 male; 46%) and 48 controls (21 male; 44%) were 10 (2-17) years and 9 (3-17) years, respectively. Mean follow-up duration was 3 years, ranging from 1-10 years. All CD patients had positive tTG-IgA and EMA-IgA tests while it was negative in all (100 %) control patients. The absolute number of circulating CD16+ NK cells (259.52 vs. 1404.36 μ/L) and CD56+ NK cells (366.24 vs. 2440.46 μ/L) were significantly lower in the celiac group than the control group (P<0.05 for both). The absolute numbers of circulating white blood cells (7785 vs. 8165 μ/L) and lymphocytes (3106 vs. 3173 μ/L) were not significantly different between the celiac and control groups (P>0.05 for both). Correlation analysis between the absolute number of circulating NK cells and tTG-IgA, tTG-IgG, and EMA-IgA levels in CD patients revealed no significant relationships (P>0.05 for all). Conclusions Peripheral blood NK cell count were significantly lower in celiac patients than controls, hence, decreased NK cell counts may be an abnormal feature seen in autoimmune diseases. NK cell count in celiac patients had no significant correlations to tTG-IgA, tTG-IgG, or EMA-IgA levels. Therefore, NK cell count may be inappropriate marker for monitoring compliance to a gluten free diet.

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Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcγRIIIa-158 V/V and V/F polymorphism

Blood ◽

10.1182/blood-2007-01-070656 ◽

2007 ◽

Vol 110 (7) ◽

pp. 2561-2564 ◽

Cited By ~ 163

Author(s):

Evdoxia Hatjiharissi ◽

Lian Xu ◽

Daniel Ditzel Santos ◽

Zachary R. Hunter ◽

Bryan T. Ciccarelli ◽

...

Keyword(s):

Cell Surface ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Gene Transcript ◽

Non Hodgkin Lymphoma ◽

Healthy Donors ◽

Cd16 Expression ◽

Cell Expression

The presence of valine (V) at position 158 of FcγRllla (CD16) is known to improve clinical response to rituximab in indolent non-Hodgkin lymphoma (NHL). Little is known about the basic mechanisms for this observation. We examined natural killer (NK) cells from healthy donors representing the FcγRIIIa-158 polymorphic subgroups (V/V, V/F, and F/F) for gene transcript and cell surface CD16 expression, rituximab binding, and rituximab-dependent NK cell-mediated cytotoxicity. We observed higher levels of FcγRIIIa transcripts among individuals with the FcγRIIIa-158 V/V versus V/F or F/F genotype (P < .001); increased cell surface CD16 expression by quantitative flow cytometry on NK cells from individuals expressing at least one valine at FcγRIIIa-158 versus F/F (P = .029); as well as augmented rituximab binding and rituximab-mediated, antibody-dependent cellular cytotoxicity (ADCC). These results suggest that individuals expressing at least one valine at FcγRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated ADCC.

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