Development of hyporesponsiveness to augmentation of natural killer cell activity after multiple doses of maleic anhydride divinyl ether: Association with decreased numbers of large granular lymphocytes

Abstract

A single injection of mice with maleic anhydride divinyl ether (MVE-2) resulted in significantly augmented natural killer (NK) activity. However, multiple injections with MVE-2 led to a hyporesponsive to boosting of NK activity. Stimulation of prostaglandin E secretion of induction of suppressor macrophages (Mø) or lymphocytes were shown not to be responsible for the depressed NK cell responses. Rather the hyporesponsiveness to NK boosting was associated with a decreased number of large granular lymphocytes (LGLs). Percoll discontinuousdensity-gradient studies showed that the augmented NK activity of spleen cells after a single injection with MVE-2 was associated with an increase in the percentage of LGLs in the lowerdensity fractions (Fraction 1 and 2). In contrast, the NK activity and percentage of LGLs in the lower-density fractions were markedly decreased after multiple injections with MVE-2. Polyinosinic: polycytidylic acid stabilized with poly( l-lysine) in carboxymethylcellulose, another BRM capable of augmenting NK activity, was able to substantially augment NK activity in mice hyporesponsive to MVE-2 and this was accompanied by an increase in the percentage of LGLs in the lower-density Percoll fractions.