Altered Th1/Th2 balance associated with the immunosuppressive/protective effect of the H-2A(b) allele on the response to allo-4-hydroxyphenylpyruvate dioxygenase

The H-2A(b) allele exerts a dominant down-regulatory effect on the anti-allo-HPPD (4-hydroxyphenylpyruvate dioxygenase) antibody response, through a hitherto unknown mechanism. In the present study, the allo-variable peptide bound to responder H-2A(k) molecules with higher affinity than to H-2A(b) ones, arguing against the operation of an affinity hierarchy. Quantitative polymerase chain reaction revealed differences in cytokine mRNA expression between suppressed and high-responder mice. Lymph node cells of responder but not suppressed mice contained high levels of interleukin (IL)-4 mRNA as early as 11 h post-immunization and continued to do so for at least 8 days; this early burst was paralleled by a small burst in transforming growth factor (TGF)-beta mRNA level. Differences in IL-12 mRNA were not detected, although an early IL-12 effect could not be excluded. Interferon (IFN)-gamma appeared to contribute to the suppression at later time points. Early treatment of responder mice with anti-IL-4 monoclonal antibody (11B11) down-regulated the antibody response. The proliferative T cell response from hyperimmunized mice was reduced but still detectable in the presence of an H-2A(b) allele. Thus, in the presence of this allele, the Th1 response is enhanced and that of Th2 cells suppressed, apparently as a result of the bias of H-2A(b)-restricted T cells in favor of the Th1 subset.