Deregulation of mouse antibody-forming cells in vivo in cell culture by streptococcal pyrogenic exotoxin.

An unregulated, elevated rebound of antibody levels in rabbits was shown to follow late (10 to 15 days) after steptococcal pyrogenic exotoxin (SPE)-induced immunosuppression. Because of that result we have suggested that SPE acts by preferentially inhibiting a regulatory cell which normally limits the extent of full expression of antibody formation by B-cells. We are currently testing this hypothesis in mice. NIH (Swiss Webster) mice (+/+) or NIH (Swiss Webster) mice heterozygous (+/nu) for the mutant athymic nude gene and phenotypically normal showed an elevated plaque-forming cell (PFC) response to sheep erythrocytes (SE) late (10 to 15 days) after immunosuppressive SPE treatment similar to that described in rabbits. Homozygous nude mice (nu/nu) that are phenotypically athymic normally show a reduced early (4 day) PFC response to SE (a T-cell-dependent antigen) as compared with +/nu littermates or +/+ parent strain mice. This cryptic early 4-day response was improved by injection of purified endotoxin (a B-cell mitogen), but these relatively elevated nude PFC responses had decreased to normal control (SE only)nude PFC levels before 10 days. In similar SE-injected nude mice treated instead with SPE, no elevation at 4 days was observed and, more pertinently, the late (10 to 15 day) elevated rebound of PFC levels observed in normal response controls (+/nu or +/+) was not observed. Similar experiments were subsequently conducted in Marbrook-type spleen PFC cultures during periods of 12 days. The results of these experiments paralleled the in vivo results above, and in addition showed that SPE induced a large proliferation of either +/+ or +/nu cells (T-and B-cells) in culture but had no such effect on nu/nu cells (B-cells) in culture. Purified endotoxin, the Bcell mitogen, had a better sparing effect on nu/nu cells in this respect. These results are consistent with our premise that SPE inhibits preferentially the function of a regulator of the antibody response. The regulator appears to be a T-cell and is likely a suppressor T-cell.