Mechanism of induction of immunological tolerance. II. Simultaneous development of priming and tolerance.

Abstract

SummaryPrevious work has shown that multiple injections of flagellar antigens into rats, starting at birth, can induce Immunological tolerance. In the present paper we have examined in some detail the effects of single, neonatal antigen injections on subsequent immune reactivity. The soluble, monomeric form of flagellin fails to induce detectable IgM antibody formation in tolerant or normal adult rats, in contrast to polymerized flagellin which, particularly in high dosage, causes brisk IgM responses. Utilizing this fact, we have shown that single neonatal injections of polymerized flagellin can lead to a substantial degree of tolerance as tested by adult monomer challenge, and also to some memory or priming as tested by adult polymer challenge. Polymerized flagellin can both prime and induce tolerance; monomeric flagellin gives less priming and perhaps slightly less tolerance.Multiple injections of antigen over the neonatal period can enhance the tolerance and eliminate the priming, and both monomer or polymer are effective when given repeatedly in a dose of 10 μg. Animals rendered completely tolerant by monomer injections retain some slight reactivity to polymer which manifests itself as a brief phase of IgM antibody production. Animals receiving multiple polymer injections do not show this if the course is maintained for 10 weeks.The apparently opposite effects of priming and tolerance induction induced by neonatal injections are speculatively explained by the hypothesis that the single antigen pulse drives some lymphoid cells (x cells) towards tolerance, others to memory (y cells). The memory cells may undergo a transient phase of susceptibility to antigen during which a second contact kills them. Thus, a single neonatal injection causes a reduction in the x cell population but also creates some y cells. A multiple injection protocol can cause a virtually total depletion of the x cell pool without causing y cell accumulation.The results and hypotheses are contrasted with Mitchison's (1964) findings in an adult tolerance model system.