Mechanisms of tolerance to HGG induced in neonatal and adult mice.

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In 1973 we repeated some of the experiments initially carried out by Chiller, Weigle, and their colleagues (Chiller et al., 1974) by attempting to terminate the tolerant state to human γ-globulin (HGG) induced in adult A/J mice by reconstitution with normal or immune lymphocytes or by the injection of crossreacting γ-globulin. We found the same results, i.e. that it was nor possible to terminate this tolerant state by either method. One would have thought that if clonal deletion was the sole mechanism responsible for this tolerance, that by providing the missing specific lymphocyte, these mice could be reconstituted to a fully normal status. Both of these methods were highly successful in terminating the tolerance to bovine serum albumin (BSA) induced in neonatal rabbits (Benjamin and Weigle, 1970; Benjamin, 1974). The results obtained in the attempts to terminate this HGG tolerance with heterologous γ-glob-ulins made us suspect that there was much more involved than the simple deletion of HGG-specific clones. The data shown in Table I illustrate this point quite well. Adult A/J male mice that had been injected with 2.5 mg deaggregated HGG (DHGG) do not respond to subsequent injections of aggregated HGG (AHGG) (Group 2), nor is this tolerant state terminated by the injection of aggregated bovine γ-globulin (ABGG) (Group 3). In fact the response of such HGG tolerant mice to the specific determinants on BGG is much reduced (compare the BGG response of Groups 3 and 4 — Table I). The reverse is also true, i.e. mice tolerant to BGG do not respond well to HGG specific determinants. Ruben et al. (1973) attributed this lack of response to non-crossreacting determinants to the loss of crossreactive T-helper cells in these HGG tolerant mice. However, it seemed to us that it could also have been due to the presence of crossreactive suppressor cells induced by the injection of tolerogen.