N Vitro Ii . a New Approach to Tiie Phenomenon of Immunological Tolerance

Some antigens may induce immunological tolerance not only after injection of high doses (high zone tolerance) but also after injection of subimmunogenic doses (low zone tolerance) (1). Although it is generally agreed that the phenomenon of tolerance results from an effect of antigen on immunocompetent cells, very little is known of the underlying mechanism. In this respect, the phenomenon of low zone tolerance is particularly difficult to understand. Striking examples of the induction of low zone tolerance in rats to H antigens of Salmonella adelaide have been reported by Shellam and Nossal (2) and by Ada and Parish (3). They have shown that the repeated injection of flagellin into new born rats (2) or of fragment A (separated from the cyanogen-bromide digest of flagellin) into adult rats (3) at doses of less than 1 pgl led to significant tolerance to subsequent challenge with the highly immuno-genic polymerized flagellin. It was calculated by the authors (2, 3) that, under the conditions used, the probability of direct interaction between antigen and immuno-competent cells in the animal at any given time during low zone tolerance induction was extremely small. From their studies of antigen localization, Ada and Parish have postulated that this probability could be increased if the assumption was made that, during low zone tolerance induction, antigen might be concentrated in distinct areas such as lymphoid follicles, provided that these areas represent sites in the pathway of the lymphoid cell circulatory system (3). However, the local antigen concentration reached in a lymphoid follicle of a lymph node draining the injection site during the induction of low zone tolerance in adult animals is still far below the dose necessary to induce high zone tolerance. At the cellular level, it is necessary to postulate