Human natural killer cells in health and disease.

Department of Pediatrics, Columbia University, New York, New York, USA.
Pediatric Blood & Cancer (Impact Factor: 2.35). 11/2007; 49(5):615-23. DOI: 10.1002/pbc.21158
Source: PubMed

ABSTRACT Natural killer (NK) cells are an essential component of the innate immune system and play a critical role in tumor immune surveillance. NK cells express their own repertoire of receptors (NKRs) that bind to major histocompatibility class I or class I-like molecules. The balance of signals from stimulation or inhibition of NKRs determines the ability of NK cells to lyse specific targets. In haploidentical stem cell transplantation with purified stem cells, NK cell alloreactivity (killer immunoglobulin-like receptor [KIR] mismatch) has been demonstrated to reduce the risk of relapse in acute myeloid leukemia. There is a need for adequately powered prospective randomized studies to determine the usefulness of NK cells as adoptive immunotherapy, optimal NK cell doses and timing of administration. Further studies are required to determine optimal selection of donors and recipients, both on NKR matching/mismatching, undergoing haploidentical and unrelated hematopoetic stem cell transplantation.

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    ABSTRACT: In adults, hepatic complications following allogeneic hematopoietic stem cell transplantation (AlloHSCT) are associated with significant morbidity and transplant related mortality (TRM). However, there is a paucity of parallel data on the incidence of, and risk factors for, liver injury (LI) and the impact of LI on TRM in pediatric AlloHSCT recipients. Methods: We compared total bilirubin, direct bilirubin and alanine aminotransferase values pre-AlloHSCT and at 1 month, day +100 and 12 months post-AlloHSCT in 248 patients following myeloablative conditioning (MAC) or reduced toxicity/reduced intensity conditioning (RTC/RIC). Liver injury was defined as ≥ Grade 2 total hyperbilirubinemia according to the NCI CTCAE 3.0/4.0 ( total bilirubin >1.95mg/dL ,1.5 times above upper limit of normal for our laboratory). Univariate and multivariate logistic regression models were used to identify risk factors for the incidences of LI and TRM. Results: 248 eligible patients received MAC (n=109) or RTC/RIC AlloHSCT (n=139). The incidence of LI at 1 month post-AlloSCT was 14.1%; median bilirubin level 3.5mg/dl (range 1.97 - 32.2). Only LI as defined by total bilirubin but not direct bilirubin or ALT was found to be a significant predictor for TRM. The 1-year TRM among patients with LI at 1 month post-AlloHSCT was 60.7% (CI95 42.6%, 78.7%) as compared to 14.6% (CI95 9.9%, 19.4%) (p<.0001) for those who did not have LI at 1 month post- AlloHSCT. On multivariate analysis, age (p=0.03), total body irradiation (p=0.007), bloodstream bacterial infections (p=0.001) and invasive fungal infections (p=0.002) were significant risk factors for developing LI at 1 month. On multivariate analysis for risk factors for TRM, only LI at 1 month post-AlloHSCT (p<0.0001), primary graft failure (p=0.001), bloodstream bacterial infections (p=.003) and systemic viral infections (p=0.04) were significant. Importantly, LI prior to AlloHSCT conditioning was not associated with higher TRM. Conclusions: TAlthough the incidence of LI in pediatric recipients of AlloHSCT is low, it is associated with very high TRM. BBSI and IFI were identified as the primary risk factors for LI.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2013; · 3.15 Impact Factor
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    ABSTRACT: Natural killer (NK) cells have a specialized function in peripheral organs, which is determined by the organ-specific niches. We have attempted to explore whether lung NK cells display a particular phenotype according to their function in the unique pulmonary environment in health or during respiratory infection in mice. In healthy mice, higher frequencies of NK cells among lymphocytes were detected in the lung than in other tissues (lymph node, bone marrow, spleen, blood and liver), and lung NK cells maintained a more mature phenotype, implying that lung NK cells were critical for the pulmonary immune response. However, lung NK cells expressed higher levels of inhibitory receptors and lower levels of activating receptors, migration/adhesion-associated molecules and co-stimulatory molecules than splenic NK cells, implying that lung NK cells were quiescent, and the activation of lung NK cells was tightly regulated by the pulmonary environment in health. During respiratory infection, lung NK cells could be activated and express functional molecules (CD107a and interferon-γ) to take part in the response to infection quickly. These results suggested that the unique pulmonary environment promotes the development of NK cells with a lung-specific phenotype.
    Immunology 05/2012; 137(1):37-47. · 3.71 Impact Factor
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    ABSTRACT: Although reduced natural killer (NK) cell levels have been reported consistently in patients with coronary artery disease (CAD), the clinical significance and persistence of this immune perturbation is not clarified. In this study we characterized the NK cell deficit further by determining (i) differentiation surface markers and cytokine profile of NK cell subsets and (ii) ability to reconstitute NK cell levels over time. Flow cytometry was used to analyse NK cell subsets and the intracellular cytokine profile in 31 patients with non-ST elevation myocardial infarction (non-STEMI), 34 patients with stable angina (SA) and 37 healthy controls. In blood collected prior to coronary angiography, the proportions of NK cells were reduced significantly in non-STEMI and SA patients compared with controls, whereas NK cell subset analyses or cytokine profile measurements did not reveal any differences across groups. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of metabolic syndrome. Moreover, interleukin (IL)-6 levels remained high in patients with sustained NK cell deficit, whereas a decline in IL-6 (P < 0·001) was seen in patients with a pronounced increase in NK cells. In conclusion, we found no evidence that reduction of NK cells in CAD patients was associated with aberrations in NK cell phenotype at any clinical stage of the disease. Conversely, failure to reconstitute NK cell levels was associated with a persistent low-grade inflammation, suggesting a protective role of NK cells in CAD.
    Clinical & Experimental Immunology 01/2014; 175(1):104-12. · 3.41 Impact Factor


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