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  • br Cytokines and NK cells br


    Cytokines and NK cells
    Combined effects of cytokines and other stimuli on NK cell function Cytokine-stimulated NK Proteinase K have enhanced capacity to kill tumor cells. However, usually, individual cytokines do not seem to be sufficient for full activation, proliferation, survival and effector functions of NK cells. In contrast, combination of different cytokines has been shown to promote NK cell cytotoxicity involving both perforin and Fas-mediated killing of tumor cells, as well as the production of IFNγ through which NK cells participate in a complex interaction network with Th1 lymphocytes, DC and macrophages to effectively direct the antitumor immune response [158]. Human NK cells with a history of prior activation with combinations of IL-12/15/18 have a capacity for cytokine-induced memory after re-stimulation with other cytokines or a tumor target cell line [159]. Such NK cells have enhanced proliferation, IFN-γ production and cytotoxicity. Memory-like NK cells upregulate CD25 (IL-2Rα) expression (resulting in expression of the heterotrimeric high affinity IL-2Rαβγ) and enhanced response to low-doses of IL-2 [160]. It have been found that memory-like NK cells show increased expression of the activating receptors NKG2D, NKp44, NKp30, NKp46 and TRAIL, but also enhanced expression of the inhibitory receptor NKG2A [27]. It has been shown that human memory-like cells when transferred to immunodeficient mice, substantially reduced the acute myeloid leukemia (AML) burden in vivo and improved overall survival. In the first phase of clinical trials in AML patients, adoptively transferred memory-like NK cells proliferated and demonstrated considerable anti-leukemia effect. Therefore, it may be concluded that in cancer patients, the inflammatory cytokines IL-12, IL-15, and IL-18 that are induced by chemotherapy, radiotherapy or HCT represent potential settings for memory-like NK cell induction in vivo. Thus, further investigations of cytokine-induced memory-like NK cells may aid in development of a promising translational immunotherapy approach for patients with hematological malignancies [161]. The combined effects of cytokines should be taken into consideration when designing cytokine-based immunotherapy for cancer patients which should not only focus on the ability of NK cells to degranulate and kill tumor targets, but also to enhance antitumor immunity through such indirect mechanisms such as cytokine production [162], [163]. Considering that immunosuppressive cytokines and other factors produced by the tumor can negatively influence NK cell function and allow tumor evasion and progression, blockade of inhibitory cytokines by monoclonal antibodies and antagonists, as well as by interference with their signaling molecules appears as a feasible therapeutic approach to enhance NK cell responses in cancer patients [164].
    Conflict of interest
    Acknowledgments This work was supported by the grants of the Ministry of Education, Science and Technological Development of the Republic of Serbia, numbers III41031 and 175056.
    Introduction In recent years, the rate of Caesarean section (C-section) delivery has significantly increased [1], [2]. Proteinase K Multiple studies indicate that C-section is a risk factor for immune-related disorders [3], [4], [5], [6]. The process of birth itself has gained attention as an immune programming event [7]. Hence the impact of mode of delivery on innate immunity of infants needs to be better understood. Recent literature suggests that the process of normal delivery stimulates the respiratory, metabolic and immunological maturation in infants which prepares them to adapt to the outside world (the exposome) [8]. The mode of delivery is known to influence the innate immune system through altered gut microbiota and hormonal changes during birth like increased catecholamines and cortisol [2], although the role of stress hormones in immune maturation is not clear [7]. A recent study also reported lower monocytes and neutrophils in cord blood of C-section delivered compared to vaginally born infants [9].