Augmentation of organ-associated natural killer activity by biological response modifiers. Isolation and characterization of large granular lymphocytes from the liver.

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Abstract
Natural killer (NK) activity in the rat and human was attributed to cells having the morphology of large granular lymphocytes (LGL). This association was less clear in the mouse, largely because of difficulties in obtaining highly enriched populations of LGL from normal spleen and blood. The administration of the biological response modifier (BRM) maleic anhydride divinyl ether (MVE-2) strongly augments NK activity in lung and liver, and the augmented NK activity coincides with increased resistance to the formation of experimental metastases in these organs. The degree of NK augmentation is most striking in the liver, an unexpected and previously unreported observation. In the study, both MVE-2 or Corynebacterium parvum [Propionibacterium acnes] induced a dramatic augmentation of liver NK activity, which reached maximum levels 3-5 d [day] after treatment. This augmentation of NK activity in the liver coincided with a large increase in the number of lymphoid cells with the morphological characteristics of LGL that could be isolated from enzymatically digested suspensions of perfused liver. The yield of LGL per liver following BRM treatment corresponded to a 10- to 50-fold increase as compared to normal mice. LGL were purified from these enzymatically digested suspensions of perfused liver by depletion of adherent cells on nylon wool columns and subsequent enrichment for low-density lymphoid cells by fractionation on Percoll density gradients. The enrichment of LGL correlated with greatly increased NK activity against [mouse lymphoma] YAC-1. Conversely, the higher-density fractions were depleted of both LGL and NK activity. This increase in NK activity in the liver was suppressed by in vivo treatment with anti-asialo GM1 (asGM1) serum. This treatment also resulted in a corresponding reduction in both the total number and percentage of LGL. By flow cytometry analysis, the phenotype of the majority of these highly cytolytic LGL isolated from the livers of BRM-treated mice were asGM1+, Thy-1+, Ly-5+, Qa-5+, Mac-1+, and Gma-1+, whereas these LGL were Ly-1-, Lyt-2-, L3T4-, and surface Ig-. The livers of BRM-treated mice can provide a rich source of highly active mouse LGL that could be used for further characterization of this lymphocyte subset. The studies imply a potential for BRM therapy of neoplastic or viral diseases through augmentation of organ-associated immune responses.