Maintenance therapy with histamine plus IL-2 induces a striking expansion of two CD56^bright NK cell subpopulations in patients with acute myeloid leukemia and supports their activation

Histamine dihydrochloride (HDC) plus IL-2 has been proposed as a novel maintenance-immunotherapy in acute myeloid leukemia (AML). We analyzed the immunophenotype and function of natural killer (NK) cells in blood of AML patients treated after chemotherapy with HDC plus IL-2. The treatment caused a striking expansion of CD56^brightCD16^neg and CD56^brightCD16^low NK cell subpopulations. A reduced NK cell fraction recovered and high proportions of cells expressed the activating receptors NKG2D, NKp30, and NKp46. Concomitantly, KIR-expressing NK cells were reduced and NK cells with inhibitory NKG2A/CD94 receptors increased beyond normal levels. In addition, the immunotherapy-induced NK cells exhibited high capacity to produce IFN-η and to degranulate. Furthermore, we provide evidence from subsequent in vitro studies that this is caused in part by direct effects of IL-2 on the CD56^bright cells. IL-2 specifically induced proliferation of both CD56bright subpopulations, but not of CD56^dim cells. It further preserved the expression of activating receptors and the capacity to produce IFN-η and to degranulate. These data suggest that therapy with HDC plus IL-2 supports the reconstitution of a deficient NK cell fraction through the specific amplification of CD56^bright NK cells giving rise to a functional NK cell compartment with high potential to combat leukemic disease.