HISTAMINERGIC REGULATION OF NATURAL-KILLER CELL-MEDIATED CLEARANCE OFTUMOR-CELLS IN MICE

Treatment of Swiss albino mice with histamine enhanced the clearance o f natural killer (NK)-cell sensitive YAC-1 lymphoma and B16/F10 melano ma 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 Hz-type histamine receptors (H(2)R) since it was blocked by ranitidine, an H(2)R antagonist. Histamine did not a ffect clearance of tumour cells in animals depleted of NK cells in viv o by treatment with antibodies to asialo-GM1 or NK1.1. The effect of h istamine was time-dependent: pretreatment with histamine for 3 h signi ficantly augmented the clearance of YAC-1 cells, whereas, pretreatment with histamine for 5 min was ineffective. Histamine potentiated the a nti-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 wer e concomitantly treated with histamine. Treatment with ranitidine alon e 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 ran itidine on NK-cell function in vivo were not shared by a chemical cont rol to ranitidine, AH20239AA, thus indicating that the inhibition of N K-cells results from H(2)R antagonism rather than non-specific toxicit y. It is concluded that histaminergic mechanisms may be involved in th e regulation of NK cell function in vivo.