MODULATION OF HLA-DQ-RESTRICTED COLLAGEN-INDUCED ARTHRITIS BY HLA-DRB1 POLYMORPHISM

Mouse class II-deficient HLA-DQB10302, DQA1*0301 (DQ8) transgenic mic e are susceptible to severe collagen-induced arthritis (CIA), an anima l model for rheumatoid arthritis. To examine whether polymorphism at t he DRB1 locus can modulate DQ-restricted arthritis, we generated doubl e-transgenic (DR/DQ) mice. HLA-DRB11502 (DR2) and DRB1*0301 (DR3) wer e introduced separately into CIA susceptible DQ8.A(beta)degrees transg enic mice to generate DQ8/DR2.A(beta)degrees and DQ8/ DR3.A(beta)degre es mice. The HLA-DR molecules in these mice were found to be functiona l on the basis of their positive/negative selection of the V-beta T ce ll repertoire. Introduction of the DR2 gene led to a significant decre ase in disease incidence in DQ8.A(beta)degrees mice, while the DR3 tra nsgene had no effect. In vitro T cell proliferative responses against bovine CII collagen in primed mice were higher in DQ8/DR3 mice compare d with DQ8/DR2 mice. Cytokine analysis showed a T(h)2 profile in DQ8/D R2 mice, while DQ8/DR3 mice showed a T(h)1 profile. These results sugg est that DRB1 polymorphism can modulate the disease.