THE ANTI-DEXTRAN RESPONSE OF SCID MICE TRANSGENIC FOR THE HEAVY-CHAINOF A DEXTRAN SPECIFIC IGM ANTIBODY

Mice homozygous for the scid mutation bear a severe defect in their ab ility to rearrange V(D)J gene segments to yield active genes for immun oglobulin and T cell receptor molecules. In older animals few clones o f B and T cells can arise at random, a phenomenon called leakyness of the acid mutation. We established scid mice carrying as a transgene th e rearranged heavy chain of the IgM/lambda(1) antibody MOPC 104E with specificity for the alpha(1,3) glucosidic linkages in Dextran. Despite the scid defect one-third of these mice immunized with the thymus ind ependent antigen Dextran at 2 weeks of age, and all of those immunized at 6 weeks responded with anti-Dextran antibodies bearing the lambda light chain. This indicates that despite the scid mutation these anima ls had at least once successfully rearranged their endogenous lambda(1 ) light chain gene segments and harbor Dextran specific B cells. These mice thus provided for the first time the opportunity to study the im mune response of B cells of a single specificity in an environment tha t should, as we shall argue, be devoid of regulatory B and T cells abl e to recognize the idiotype of the responding cells. One week after im munization the anti-Dextran response of 5- to 6-week-old mu-transgenic scid mice amounted to 30% of the response of mu-transgenic non-scid m ice but in essence both responses followed the same kinetics, reaching antibody concentrations indistinguishable from each other 8 weeks aft er a single dose of Dextran. Furthermore, the ready response of young mu-transgenic scid mice to this antigen by employment of endogenously rearranged lambda(1) fight chains allowed experiments to be done to co mpare the frequency of lambda(1) light chain rearrangements in p-trans genic acid mice to that in mu-transgenic non-scid mice. This was done in limiting dilution assays counting B cell precursors responsive to m itogen and differentiating in vitro to produce antibodies toward Dextr an. Specific precursors were reduced to about 1% in the spleen of mu-t ransgenic scid mice when compared to the spleen of mu-transgenic non-s cid mice; those in the peritoneal cavity lymphocyte population were re duced to about 12%. (C) 1996 Academic Press, Inc.