INDUCTION OF TOLERANCE TO HUMAN GAMMA-GLOBULIN IN FCR-GAMMA-DEFICIENTAND FC-GAMMA-RII-DEFICIENT MICE

FcR gamma-deficient mice were used to examine the role of Fc gamma rec eptors in the induction of peripheral tolerance to human gamma-globuli n (HCC), FcR gamma-deficient mice injected with HCC in adjuvant demons trated a CD4(+) T cell response to in vitro challenge with HCG, as ass ayed by proliferation, cytokine secretion, and Ag-specific help for B cell Ab production, In vitro kinetics of Ag-specific proliferation wer e similar in both conventional and knockout mice, Peripheral tolerance could be established in these mice with a single dose of deaggregated protein, despite the lack of functional Fc gamma RI, the high affinit y receptor for monomeric Igc, Establishment of unresponsiveness was ob served at both the T and B cell levels, T cell tolerance was manifeste d in the reduction of T cell helper function and Ag-induced release of Th1- and Th2-like cytokines, as well as decreased proliferation to Ag -specific stimulation, B cell tolerance was demonstrated in knockout a nd normal mice by failure to detect HGG-specific Ab production using a n immunization protocol for Ab production that bypasses the need for A g-specific T cells, These results demonstrate that induction of tolera nce in CD4(+) cells to HCC does not require transduction of a signal t hrough Fc gamma RI, Furthermore, the ability to induce tolerance to HG G in B cells in Fc gamma RII-deficient mice suggests that down-regulat ion of Ag-specific B cells through Fc gamma RII is not the mechanism b y which B cell tolerance is induced, However, Fc gamma RII plays a rol e in regulating the immune response since the Ab response to immunogen ic HGG in Fc gamma RII-deficient mice is markedly enhanced.