No abstract

and low responder lines of mice biology, Wellcome Research Laboratories, BeckenhamDose response curves for two thymus-independent branched polysaccharides, levan and dextran B 1355, have been compared by direct plaque-forming cell assays in the Biozzi high (Ab/H) and low (Ab/L) responder lines of mice.In contrast with all of many other antigens so far tested, equivalent IgM responses were elicited by native levan (mol. wt. 2 x lo7), Pseudomonas levanicum vaccine and native dextran (mol. wt. 4 x lo7). Partially depolymerized levan (mol. wt. 5 x lo4 -7 x lo4) was surprisingly more immunogenic in Ab/L than in Ab/H mice. Furthermore, the tolerance threshold dose of both native and depolymerized levans was lower in the Ab/H line, the converse of previous findings with the linear polysaccharide SIII. Equivalent anti-DNP responses were obtained in the two lines when they were immunized with t h e hapten conjugated with levan, whereas conventional high/low separation was obtained when polymerized flagellin was used as carrier.It is concluded that nonspecific "high" and "low" responsiveness in Ab/H and Ab/L mice results not from a n intrinsic difference in their B cells, but from selective inyolvement of a n extrinsic regulation mechanism. Evidence which implicates divergence in antigen handling by macrophages as a primary factor, and the exceptional behavior of the branched polysaccharides in evading this difference are discussed.

Mice immunized with an optimal (10 pg), but not suboptimal, dose of levan (LE) became specifically unresponsive to a second dose given 2-8 weeks later. No evidence which could implicate an active suppression mechanism was found. In particular (a) spleen cells from unresponsive donors did not inhibit normal cells in a transfer system; (b) equilibration of serum antibody following 2 days celomic parabiosis between LE-treated and normal mice did not impair responsiveness of the latter, It was concluded that B cells were exhausted in the absence of memory cell accumulation. LE can therefore induce specific B cell deletion, not only directly with 1 mg, but also following immunization with 10 pg. The exhaustive capacity of another polysaccharide, SIII, was found to be much weaker.Cyclophosphamide (CP) ( 150 mg/kg) completely suppressed the responses to LE and SIII when injected with them. Recovery following CP alone was nearly complete 2 weeks later, but simultaneous injection of an immunizing amount of LE was succeeded by dose-related specific tolerance. Total suppression followed only 100 ng LE + CP, a 10 000-fold reduction in the "high zone" tolerizing dose. The corresponding reduction in SIII experiments was onlyThe times for recovery following transfer of spleen cells from donors tolerant of LE in the exhaustion and CP models were 2 and 4 weeks, respectively; periods commensurate with B cell renewal.The basis for these further differences in the tolerogenic properties of LE and Sfold.SIII are discussed,