Regulation of murine IgE responses: induction of long-lived inhibition of allergen-specific responses is genetically restricted.

We previously reported that administration of high Mr glutaraldehyde-polymerized ovalbumin (OA-POL) 10 days prior to OA Al(OH)3 immunization results in 85 to 99% inhibition of primary and secondary anti-OA IgE responses and 10(2)- to 10(4)-fold increases in OA-specific IgG2a production in each of 14 inbred and 1 outbred murine strains tested. Administration of unmodified OA under the same conditions fails to inhibit IgE synthesis and yields only minor increases in IgG2a production. In the present report, the genetic restrictions placed on the capacity of this modified allergen to elicit long-lived reciprocal regulation of specific IgE and IgG2a responses were examined. Virtually permanent, antigen-specific inhibition of IgE production (greater than 90% for greater than 22 months) was elicited in C57B1/6 mice following administration of a single course of OA-POL. This inhibition was paralleled by substantial (250-fold) increases in specific IgG2a production and was dependent on the activity of extremely long-lived regulatory CD4 T cells. In contrast, BALB/c mice failed to maintain an IgE unresponsive state beyond 10-12 weeks and exhibited transient and less intense increases in IgG2a production. Examination of MHC and Igh congenic strains revealed that the induction of long-term split tolerance by these modified allergens is under multigenic control and is not solely attributable to MHC, Igh, or background genes.