NK cell‐mediated killing of AML blasts: role of histamine, monocytes and reactive oxygen metabolites

Abstract

Blasts recovered from patients with acute myelogenous leukaemia (AML) were lysed by heterologous natural killer (NK) cells treated with NK cell‐activating cytokines such as interleukin‐2 (IL‐2) or interferon‐α (IFN‐α). The cytokine‐induced killing of AML blasts was inhibited by monocytes, recovered from peripheral blood by counterflow centrifugal elutriation. Histamine, at concentrations exceeding 0.1 μM, abrogated the monocyte‐induced inhibition of NK cells; thereby, histamine and IL‐2 or histamine and IFN‐α synergistically induced NK cell‐mediated destruction of AML blasts. The effect of histamine was completely blocked by the histamine H2‐receptor (H2R) antagonist ranitidine but not by its chemical control AH20399AA. Catalase, a scavenger of reactive oxygen metabolites (ROM), reversed the monocyte‐induced inhibition of NK cell‐mediated killing of blast cells, indicating that the inhibitory signal was mediated by products of the respiratory burst of monocytes. It is concluded that (i) monocytes inhibit anti‐leukemic properties of NK cells, (ii) the inhibition is conveyed by monocyte‐derived ROM, and (iii) histamine reverses the inhibitory signal and, thereby, synergizes with NK cell‐activating cytokines to induce killing of AML blasts.

Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia

“…4,10,[38][39][40] Interest in the role of this cytokine did not subside even after an early RCT failed to demonstrate a significant benefit of IL-2 in survival outcomes in AML patients, 20 and several more RCTs ensued. [21][22][23][24][25] Results of these trials are challenging to compare at face value, given the different age groups, remission induction regimens, lengths of follow-up, number of patients discontinuing due to toxicity, and doses of IL-2 that were used.…”

l-Kynurenine-induced apoptosis in human NK cells is mediated by reactive oxygen species

“…However, several researchers have recently proposed that reactive oxygen species inhibit anticancer activity of lymphocytes and lead to cell death of cytotoxic lymphocytes [21][22][23]. Moreover, oxidative stress may lead to malfunction of NK cells as well as decrease of cell numbers in malignant disease states [22][23][24][25][26]. Based on this evidence, some studies have proposed that reactive oxygen species may have a pivotal role in the mechanism of malignant disease progression through the impairment and decrease of NK cells.…”

Histamine Promotes the Development of Monocyte-Derived Dendritic Cells and Reduces Tumor Growth by Targeting the Myeloid NADPH Oxidase

“…ROS are formed upon the assembly of the membrane-bound myeloid gp91 phox subunit NOX2 with other membrane and cytosolic components (12). By reducing the formation and extracellular release of ROS, histamine was found to preserve NK cell function and, thus, promote NK cell-mediated clearance of malignant cells under conditions of phagocyteinduced oxidative stress (9,10). These results formed the basis for the inclusion of histamine in cancer immunotherapy protocols (13).…”

“…However, the detailed mechanisms by which histamine deficiency results in the accumulation of immature myeloid cells are largely unknown. In addition to the role of histamine in myeloid cell differentiation, it has been ascribed immune-stimulatory properties by virtue of its inhibitory action on the production and release of immunosuppressive NADPH oxidase-derived reactive oxygen species (ROS) from phagocytes, such as monocytes and neutrophilic granulocytes (8)(9)(10)(11). ROS are formed upon the assembly of the membrane-bound myeloid gp91 phox subunit NOX2 with other membrane and cytosolic components (12).…”