Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). III. Circumvention of nonresponsiveness in mice bearing HBsAg nonresponder haplotypes.

Abstract

The murine humoral immune response to HBsAg has previously been demonstrated to be regulated by H-2-linked Ir genes. After i.p. immunization with HBsAg particles, HBsAg high-responder (H-2(q)) and nonresponder (H-2(s,f)) haplotypes have been identified, and this system was used to investigate the cellular mechanisms of non-responsiveness to HBsAg and methods of circumventing it in H-2(s,f) haplotype-bearing strains. First, immunization of C3H.Q (H-2(q)) responder mice with HBsAg/ad as an HBsAg-SRBC conjugate induced IgM and IgG responses to both the group-specific a and subtype-specific d determinants of HBsAg. In contrast, SJL (H-2(s)) nonresponder mice produced an IgG-only subtype-specific anti-d response, without a concomitant group-specific anti-a response. Preimmunization of SJL nonresponder mice with free HBsAg inhibited the subsequent response to HBsAg-SRBC. However, the involvement of T suppressor (Ts) cells in this phenomenon could not be confirmed by cell transfer or Ts cell-depletion experiments. Second, immunization of H-2(s) haplotype-bearing nonresponder strains with HBsAg via the hind footpads, as opposed to i.p. injection, elicited both anti-a and anti-d specific antibody production. However, the magnitude and kinetics of the humoral responses were markedly reduced and delayed relative to that of either H-2 congenic or noncongenic responder strains. Furthermore, while C3H.Q (H-2(q) responder mice demonstrated an HBsAg-specific T cell proliferative response after footpad immunization, no HBsAg-specific T cell proliferation was observed in SJL (H-2(s)) nonresponder mice, although HBsAg-specific B cell proliferation and anti-HBs were detected. Third, native HBsAg nonresponder SJL mice produced low but detectable levels of anti-HBs when immunized with synthetic peptide analogues of HBsAg determinants. These results indicate that the nonresponsive state is characterized by defective generation of HBsAg-specific T cell proliferative responses, and they minimize the influence of HBsAg-specific suppressor mechanisms. Additionally, HBsAg-specific B cell repertoires appear to be intact in nonresponder strains, so circumvention of nonresponsiveness, in terms of antibody production, can be obtained by strategies that enhance nonspecific T cell helper function.