Induction of antigen-specific immunological unresponsiveness by inhibitors of human lymphocyte-activating factor.

Antigen-stimulated blood mononuclear cells preincubated in vitro with Cd2+ or phenanthroline, a Zn2+-chelator, did not respond normally on restimulation with antigen, as judged by their ability to elaborate leucocyte migration inhibitory factor (LIF). Other divalent metal ions, including Zn2+, were ineffective. The effect was immunologically specific, since challenge of similarly pretreated cells with an unrelated antigen, to which the cells were also sensitized, resulted in normal LIF production. The lack of responsiveness could not be ascribed to cell death, carry-over of the inhibitors, or exhaustive release of LIF during the inductive phase. Phenanthroline and Cd2+ are known to inhibit the activity of the macrophage-derived lymphocyte-activating factor (LAF), whose effect is exerted non-specifically on antigen-stimulated lymphocytes in G1. Seen in the context of a two-signal model of lymphocyte activation, it is hypothesized that immediate tolerance induction is triggered by delivery of the antigenic stimulus (signal 1) without addition of the non-specific signal 2 (LAF).