IN-VITRO INHIBITION OF NATURAL-KILLER-MEDIATED LYSIS BY CHROMATIN FRAGMENTS

A qualitative impairment of natural killer (NK) function and the prese nce of circulating DNA have been independently reported in clinical si tuations such as cancer and lupus. The existence of receptors for chro matin fragments at the leukocyte membrane raised the question of the r elation between the presence of chromatin fragments in the extracellul ar medium and the impairment of NK function. The present study shows t hat plasmas from patients with metastatic cancer and with pathological DNA concentrations inhibited significantly the NK activity of normal lymphocytes as compared to cancer plasmas with DNA concentrations in t he normal range. In vitro, it was demonstrated that chromatin fragment s inhibited the NK-mediated cytotoxicity in a dose-dependent manner. I nhibitory concentrations of nucleosomes (2.5-10 mu g/ml) were lower th an those of DNA and histones alone (100 mu g/ml). Inhibitory effects o f nucleosomes, DNA and histones differed also according to the effecto r population used: nucleosomes were effective whatever the CD56(+) cel l enrichment of the effector population, while DNA inhibition needed T cells, and histone inhibition probably resulted from a subtoxic effec t, prevented by the presence of adherent cells. Finally we found that nucleosomes could inhibit the NK function only when they were present in the extracellular medium. Taken together, these data suggest that t he persistence of nucleosomal DNA at sites of cell death or in the blo od might be responsible, at least partly, for the NK activity impairme nt observed in pathological circumstances characterized by a high rate of cell death phenomena such as cancer.