HUMAN-LEUKOCYTE ANTIGEN-DRB1-ASTERISK-1502 (DR2DW12) TRANSGENE REDUCES INCIDENCE AND SEVERITY OF ARTHRITIS IN MICE

A strong correlation exists between susceptibility to RA in humans and some DRB1 alleles of the MHC region, such as DRB10401 and DRB1*0101. Meanwhile, incidences of other DR specificities, such as DR2, DR5, or DR7 have often been found reduced among RA patients. Like RA, suscept ibility to mouse CIA is influenced by che MHC class II loci. To analyz e the effect of a DRB1 molecule associated with low incidence of RA on mouse CIA, a human DRB11502 (DR2Dw12) transgene was introduced into CIA-susceptible B10.RQB3 (H2A(q)) mice. Transgene-positive DRB11502 m ice showed a significant reduction in the incidence and severity of ar thritis. Moreover, the clinical reduction of arthritis correlated with the T-cell proliferative response of B10.RQB3-DRB11502 mice against a self-derived DRB1 peptide from the third hypervariable region. Our r esults suggest that the DRB11502-mediated protection against CIA can be explained by the DRB1 molecule acting as a source of self-antigenic peptide which interferes with the T-cell response against immunodomin ant region(s) of the arthritogenic type II collagen molecule. By analo gy, a similar mechanism might play a critical role in influencing the class II-associated predisposition to RA.