scholarly journals Dysfunction of natural killer cells in end-stage kidney disease on hemodialysis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kei Nagai

AbstractNatural killer (NK) cells are known to play an important role in defense against infection and tumors. Although there is no clear consensus, most studies have shown that the number and cytotoxicity of NK cells decreases in end-stage kidney disease (ESKD) patients undergoing hemodialysis. Uremic patients chronically suffer from oxidative stress, which could be responsible for downregulation of the activating receptors on NK cells and modulation of ligand expression for activating receptors. Theoretically, the reduced number of NK cells and decreased function might increase susceptibility to viral infections and cancer development in patients with ESKD. There is emerging evidence that NK cell numbers may be an outcome predictor in renal transplantation; however, the clinical significance of NK cell dysfunction in dialysis patients requires clarification. In this review, I describe NK cell number, cytotoxic activity, and activating mechanisms in the context of uremia and oxidative stress, which is anticipated to assist in elucidating the mechanisms underlying immunodeficiency in dialysis patients.

2021 ◽  
Vol 4 (57) ◽  
pp. 8-11
Author(s):  
Szymon Warwas ◽  
Marta Jagosz ◽  
Beata Średniawa ◽  
Michał Mazurek ◽  
Ewa Jędrzejczyk-Patej

The most common cause of death among dialysis patients with end-stage kidney disease are cardiovascular diseases. It is estimated that 18-27% of all deaths in dialysis patients are sudden cardiac deaths due to arrhythmias and conduction disturbances. The most common arrhythmias in dialysis patients, often leading to sudden death, are not ventricular arrhythmias but bradyarrhythmias. The article below discusses the most common arrhythmias in dialysis patients and methods of preventing sudden cardiac death in this group of patients.


2010 ◽  
Vol 207 (10) ◽  
pp. 2065-2072 ◽  
Author(s):  
Nathalie T. Joncker ◽  
Nataliya Shifrin ◽  
Frédéric Delebecque ◽  
David H. Raulet

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.


2020 ◽  
Vol 20 (2) ◽  
pp. 822-832 ◽  
Author(s):  
Wahyu Widowati ◽  
Diana K Jasaputra ◽  
Sutiman B Sumitro ◽  
Mochammad A Widodo ◽  
Tjandrawati Mozef ◽  
...  

Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immuno- surveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs). Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concen- trations of TNF-α and IFN-γ by NK cells with ELISA. Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion. Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells in- creased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition. Keywords: Activator; breast cancer; interleukins; natural killer; receptor.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5480-5480
Author(s):  
Isabel Gonzalez-Gascon y Marin ◽  
Ana María Pérez-Corral ◽  
Jorge Gayoso ◽  
Javier Anguita ◽  
Ana Carolina Franco ◽  
...  

Abstract Background The main functions of Natural Killer (NK) cells are early protection against viruses or tumour cells and production of cytokines that regulate immune functions. NK cells are the first lymphoid cells to repopulate the marrow after Stem Cell Transplantation (SCT) and reach normal levels within 1 month after transplant. Acquisition of both, inhibiting and activating receptors on developing NK cells is an important step in their functional maturation. Previous studies showed the beneficial effect of NK alloreactivity in prevention of relapse, especially in the setting of haploidentical SCT. The aim of this study is to compare the reconstitution of the NK cell compartment during the first 3 months after unmanipulated haploidentical peripheral blood SCT (Haplo) and HLA-identical sibling peripheral blood SCT (HLA-id). Patients and Methods 11 adult patients received SCT (7 Haplo and 4 HLA-id) at Gregorio Marañón Hospital (Madrid-Spain) from November 2012 to April 2013. Conditioning regimen comprised fludarabine, cyclophosphamide and busulfan for Haplo SCT and fludarabine and busulfan or fludaribine and melphalan for HLA-id SCT. Prophylaxis for acute graft-versus-host disease consisted of high dose cyclophosphamide on days +3 and +4, cyclosporine A and mycophenolate mofetil for Haplo and Cyclosporine A and methotrexate for HLA-id. Patient´s characteristics and transplant outcomes are shown in table 1. We analysed reconstitution patterns and phenotype of NK at day +15, +30, +60, and +90 after transplantation by multi-color flow cytometry on FC500 Beckman Coulter® cytometer using the following anti-human monoclonal antibodies: CD3 FITC, CD56 ECD, CD45 PC7, NKG2A PC7, NKp30 PC5, NKp44 PE, Nkp46 PC5, and NKG2D PE (Beckman Coulter®). For comparison between the two groups Mann–Whitney U-test was used. Results 2/7 patients who received Haplo SCT died early in the post-transplantation period (day +50 and +66), and were excluded of the analysis because NK cells were not recovered by those days. NK cells reached normal levels by day +30: median 71 cells/µl (21-1089)) after Haplo; median 213.5 cells/µl (113-499) after HLA-id, and remained at high levels through follow up, with no significant differences between the two groups. Similarly to previous studies, a large percentage of NKbright cells was observed at day +30 after Haplo (median 89% of NK cells (55-97%)), a percentage that tended to decrease at day +60 (30% (7-38%)) and +90 (35% (10-45%)). Interestingly the percentage of NKbright cells after HLA-id SCT at day +30 (median 14.5% of NK cells (6-30%)) compared with Haplo, was significantly lower (p=0.016). This was accompanied by a significantly lower expression of inhibitory receptor NKG2A after HLA-id SCT than after Haplo: 59.5% (50-62%) versus 92.5% (50-62%) at day +30; 54% (38-61%) versus 86% (70-88%) versus at day +60 (p=0.016). Activating receptors NKp44 and NKp30 showed a low expression after both types of SCT throughout the first 3 months after transplantation. By contrast, activating receptor NKp46 levels were significantly higher at day +30 after Haplo than after HLA-id SCT (93% (87-98%) versus 50% (37-51%)) (p=0.016). Finally, high and similar proportions of activating receptor NKG2D were observed in both types of SCT. Figure 1 illustrates the recovery of the NK cell receptor phenotype for each type of SCT. Conclusions Our data showed an early and fast recovery of NK cells after Haplo and HLA-id SCT. However, phenotypic maturation of NK cells appears to be different for each type of transplant. NK cells generated after Haplo exhibit a more immature phenotype, characterized by a higher proportion of NKbright cells, and a higher expression of NKG2A at day +30. Interestingly expression of NKp46 was significantly higher after Haplo than after HLA-id SCT. Other authors have reported cytotoxic activity of these NK cells with high expression of NKp46, suggesting that cytotoxicity may be preserved in these immature NK cells. NKp30, NKG2D and NKp44 expression is less affected by the type of SCT. Acknowledgments This work has been partially supported by Project “Evaluación de la reconstitución inmune después del trasplante haploidéntico de progenitores hemopoyéticos sin depleción T” from Fundación Mutua Madrileña. Disclosures: No relevant conflicts of interest to declare.


2000 ◽  
Vol 192 (7) ◽  
pp. 1059-1068 ◽  
Author(s):  
Jun Wu ◽  
Holly Cherwinski ◽  
Thomas Spies ◽  
Joseph H. Phillips ◽  
Lewis L. Lanier

Many of the activating receptors on natural killer (NK) cells are multisubunit complexes composed of ligand-binding receptors that are noncovalently associated with membrane-bound signaling adaptor proteins, including CD3ζ, FcεRIγ, DAP12, and DAP10. Because the DAP10 and DAP12 genes are closely linked, expressed in NK cells, and have remarkably similar transmembrane segments, it was of interest to determine the specificity of their interactions with ligand-binding receptors and to examine their signaling properties. Despite their similarities, DAP10, DAP12, FcεRIγ, and CD3ζ form specific receptor complexes with their ligand-binding partners in NK cells and transfectants. The transmembrane regions of DAP10 and DAP12 are sufficient to confer specific association with their partners. Although cross-linking of either DAP10- or DAP12-associated receptors has been shown to be sufficient to trigger NK cell–mediated cytotoxicity against Fc receptor–bearing cells, substantial synergy was observed in the induction of cytokine production when both receptors were engaged. Activation of the Syk/ZAP70 tyrosine kinases by the immunoreceptor tyrosine-based activation motif–containing DAP12 adaptor and of the phosphatidylinositol 3-kinase pathway by the YxNM-containing DAP10 adaptor may play an important role in the stimulation of NK cells and T cells.


2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 95-95
Author(s):  
Christine Pasero ◽  
Gwenaelle Gravis ◽  
Mathilde Guerin ◽  
Palma Rocchi ◽  
Jeanne Thomassin ◽  
...  

95 Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3007-3007 ◽  
Author(s):  
Yaya Chu ◽  
Janet Ayello ◽  
Lowrence Lo ◽  
Jared Katz ◽  
Ashlin Yahr ◽  
...  

Abstract Abstract 3007 Background: The outcome for children and adolescents with B-L/L has improved significantly but for patients who relapse or progress, the prognosis is dismal due to chemo-immuno-radiotherapy resistance (Cairo, et al, J Clin Oncol, 2012). Novel, non-chemotherapy-based therapies are desperately needed for this specific poor risk population. Natural Killer (NK) cells play an important role in tumor surveillance post allogeneic stem cell transplantation (Ruggeri L et al., Science 2002) but cell number and tumor specific recognition limit adoptive NK cell therapy (Shereck/Cairo, PBC 2007). Genetically engineered and expanded NK cells with an anti-CD19 CAR have been previously reported by Campana et al (Li L et al, Cancer Gene Ther. 2010). Anti-CD20 CAR transduced primary NK cells by retrovirus were reported by our group (Chu & Cairo, et al, ASH, 2011). Objective: To generate large-scale, efficiently modified NK cells with low cost, clinical applicable and a non-virus method, we investigated the functional activities of anti-CD20 chimeric antigen receptor (CAR+) modified PBNK cells following mRNA nucleofection against CD20+ B-L/L. Methods: PBMC were expanded with mitomycin C treated K562-mbIL15–41BBL cells for 7 or 14 days. CD56+CD3− expanded PBNK (exPBNK) cells were isolated using Miltenyi NK cell isolation kit. CD56, CD3 and receptor expression were evaluated by flow cytometry. Anti-CD20-4-1BB-CD3ζ was subcloned into a pcDNA3 vector. Anti-CD20-4-1BB-CD3ζ mRNA (CAR mRNA) was produced using the mMESSAGE mMACHINE T7 Ultra kit from T7 promoter. CAR mRNA was nucleofected into exPBNK using Amaxa nucleofector. CAR expression was detected using FITC-conjugated goat anti-mouse IgG, F(ab')2 fragment-specific antibody. exPBNK cytotoxicity was assessed by europium release assay at different E:T ratios against CD20+ B-L/L. CD107a degranulation and intracellular IFNgƒnproduction in exPBNK were measured by flow cytometry after stimulation with medium, K562-mbIL15–41BBL, CD20+ Ramos, CD20+Daudi, or CD20− RS4;11 for 4–6 hrs. Results: CD56+CD3− exPBNK cells were significantly expanded by mitomycin C treated K562-mbIL15–41BBL cells at day7. exPBNK cells were selected with more than 96% purity of CD56+CD3−. 50 to 95% exPBNK cells were detected to express CAR at 16 hrs after CAR mRNA nucleofection. CAR mRNA nucleofection did not affect the expression of exPBNK activating receptors (CD16, CD69, NKG2D, CD244, NKp30, NKp44, NKp46) or inhibitory receptors (NKG2A, KIR2DS4, CD94, CD158a, CD158b, CD158e). exPBNK in vitro cytotoxicity was significantly enhanced by CAR+ exPBNK compared to CAR− exPBNK against CD20+ B-L/L at 10:1 (n>3): Ramos (97.25+ 2.61% vs 82.5+ 4.058%, p<0.05), Daudi (71.5+ 3.26% vs 36.34+ 6.31%, p<0.001), Raji (21.45+ 1.98% vs 6.94+ 5.64%, p<0.05), Raji-2R (a Rituximab resistant cell line) (96.39+ 1.03% vs 86.3+ 1.52%, p<0.01), and U-698-M (82.84+ 1.17% vs 26.2+ 0.776%, p<0.001). However, there was no significant difference against CD20− RS4;11 or Jurkat cells. Consistently, CD107a degranulation was enhanced in CAR+ exPBNK compared to CAR− exPBNK in response to CD20+ Ramos (31.47+ 1.74% vs 15.2+ 0.26%, p<0.001, n=3) and Daudi (38.9+ 2.7% vs 19.73+ 0.58%, p<0.001, n=3) stimulation, however, there was no significant difference in response to RS4;11 or medium. Intracellular IFNγ production was also enhanced in CAR+ exPBNK compared to CAR− exPBNK in response to CD20+ Ramos and Daudi specific stimulation. We also observed that the expression of exPBNK activating receptors (CD69, NKp44 and NKG2D) were enhanced similarly and inhibitory receptors (CD94 and CD158b) were unchanged in mock exPBNK and CAR+ exPBNK cells after incubation with U-698-M compared to medium, implying CAR+PBNK directed enhanced cytotoxicity is mainly mediated by engineered CAR but not by endogenous NK receptors. Conclusion: Anti-CD20 CAR expression in exPBNK cells by mRNA nucleofection was associated with a significant increase in CD107 degradulation and INF-g production after stimulated with CD20+ BL/L compared to mock exPBNK cells. Consequently, Anti-CD20 CAR expression in exPBNK cells results in significant and specific exPBNK in vitro cytotoxicity against CD20+ B-L/L. Future directions include examining CAR+ exPBNK cytotoxic activity against CD20+ primary B-L/L tumor cells isolated from patients and testing the anti-tumor activity of CAR+ exPBNK against B-L/L and animal survival in xenograft mice. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
pp. 1-9
Author(s):  
José E. Navarrete ◽  
David C. Tong ◽  
Jason Cobb ◽  
Frederic F. Rahbari-Oskoui ◽  
Darya Hosein ◽  
...  

<b><i>Background:</i></b> End-stage kidney disease patients on dialysis are particularly susceptible to COVID-19 infection due to comorbidities, age, and logistic constraints of dialysis making social distancing difficult. We describe our experience with hospitalized dialysis patients with COVID-19 and factors associated with mortality. <b><i>Methods:</i></b> From March 1, 2020, to May 31, 2020, all dialysis patients admitted to 4 Emory Hospitals and tested for COVID-19 were identified. Sociodemographic information and clinical and laboratory data were obtained from the medical record. Death was defined as an in-hospital death or transfer to hospice for end-of-life care. Patients were followed until discharge or death. <b><i>Results:</i></b> Sixty-four dialysis patients with COVID-19 were identified. Eighty-four percent were African-American. The median age was 64 years, and 59% were males. Four patients were on peritoneal dialysis, and 60 were on hemodialysis for a median time of 3.8 years, while 31% were obese. Fever (72%), cough (61%), and diarrhea (22%) were the most common symptoms at presentation. Thirty-three percent required admission to intensive care unit, and 23% required mechanical ventilation. The median length of stay was 10 days, while 11 patients (17%) died during hospitalization and 17% were discharged to a temporary rehabilitation facility. Age &#x3e;65 years (RR 13.7, CI: 1.9–100.7), C-reactive protein &#x3e;100 mg/dL (RR 8.3, CI: 1.1–60.4), peak D-dimer &#x3e;3,000 ng/mL (RR 4.3, CI: 1.03–18.2), bilirubin &#x3e;1 mg/dL (RR 3.9, CI: 1.5–10.4), and history of peripheral vascular disease (RR 3.2, CI: 1.2–9.1) were associated with mortality. Dialysis COVID-19-infected patients were more likely to develop thromboembolic complications than those without COVID-19 (RR 3.7, CI: 1.3–10.1). <b><i>Conclusion:</i></b> In a predominantly African-American population, the mortality of end-stage kidney disease patients admitted with COVID-19 infection was 17%. Age, C-reactive protein, D-dimer, bilirubin, and history of peripheral vascular disease were associated with worse survival.


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