Histaminergic Regulation of Natural Killer Cell‐Mediated Clearance of Tumour Cells in Mice

Abstract

Treatment of Swiss albino mice with histamine enhanced the clearance of natural killer (NK)-cell sensitive YAC-1 lymphoma and B16/F10 melanoma cells from lung tissue in vivo, but did not affect the elimination of NK-cell-insensitive P815 mastocytoma cells. The effect of histamine was apparently mediated by H2-type histamine receptors (H2R) since it was blocked by ranitidine, and H2R antagonist. Histamine did not affect clearance of tumour cells in animals depleted of NK cells in vivo by treatment with antibodies to asialo-GM1 or NK1.1. The effect of histamine was time-dependent: pretreatment with histamine for 3 h significantly augmented the clearance of YAC-1 cells, whereas, pretreatment with histamine for 5 min was ineffective. Histamine potentiated the anti-tumour properties of NK-cell activators such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) in vivo. None of these lymphokines significantly affected the clearance of YAC-1 cells unless animals were concomitantly treated with histamine. Treatment with ranitidine alone reduced the in vivo clearance of YAC-1 cells from lungs but did not affect the clearance of NK-cell-insensitive P815 cells. Effects of ranitidine on NK-cell function in vivo were not shared by a chemical control to ranitidine, AH20239AA, thus indicating that the inhibition of NK-cells results from H2R antagonism rather than non-specific toxicity. It is concluded that histaminergic mechanisms may be involved in the regulation of NK cell function in vivo.

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

“…Our data support a novel treatment strategy involving the blocking of phagocyte-generated ROS by histamine, thereby protecting NK and T cells from apoptosis and, thus, synergising with IL-2 in inducing NK-and T-cell activation Asea et al, 1996;Hansson et al, 1999). Clearly, with regard to the 'good guys', treatment with IL-2/HDC resulted in significantly higher numbers of intratumoural NK and CD8 þ T cells during treatment compared with baseline.…”

“…Targeting NADPH-oxidase through binding to the H 2 -receptor on monocytes (Hellstrand and Hermodsson, 1986) and neutrophils (Betten et al, 2003), HDC specifically blocks the formation and release of hydrogen peroxide (H 2 O 2 ), thereby protecting NK and T cells from oxygen radical-induced inhibition and apoptosis (Hellstrand et al, 1994). Thus, NK and T cells remain viable and responsive to interleukin-2 (IL-2) Asea et al, 1996). IL-2 has no direct impact on tumour cells (Rosenberg, 2001) but requires NK and T-cells for tumourlysis (Donskov et al, 2002a(Donskov et al, , 2004a.…”

The response of Dunning R3327 prostatic adenocarcinoma to IL-2, histamine and radiation

“…Thereby, histamine may synergize with IL-2 to induce NK cell-mediated killing of a variety of cultured tumour cells in vitro (Hellstrand and Hermodsson, 1990;Hellstrand et al, 1994b). Treatment of mice with histamine also enhances the IL-2-induced activation of NK cells in vivo (Asea et al, 1996) and addition of histamine to conventional IL-2 therapy has shown initial promise in patients with metastatic melanoma (Hellstrand et al, 1994a) and acute myelogenous leukaemia (Brune and Hellstrand, 1996).…”

Histamine and Cytokine Therapy: Paper presented at the annual meeting of the Swedish Oncology Society, Stockholm, 1997

“…Clearance of YAC-1 cells was significantly enhanced in animals pretreated with histamine, acting via H2R, and reduced by ranitidine and other H2R antagonists (such as cimetidine, tiotidine, and famotidine). The effect of histamine on lung clearance of YAC-1-cells was completely abrogated in animals depleted of NK cells in vivo (22,31).…”

“…It was found that the addition of histamine effectively potentiated the anti-metastatic effect produced by IL-2 or IFN-h in B16 melanoma, and that treatment with histamine and IL-2 as well as with histamine and IFN-h apparently synergistically augmented the NK-cell-mediated killing of YAC-1 lymphoma cells in vivo (22,31).…”