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Abstract

Objective

To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA–DR.

Methods

Immunizing mice transgenic for the human HLA–DRB1*0101 immune response gene with CII elicits an arthritis (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263–270), recognized by T cells in the context of DR1. To produce synthetic peptides with the potential of disrupting the DR1-restricted immune response, synthetic analog peptides were developed that contain site-directed substitutions in critical positions. These peptides were used to treat CIA in DR1 transgenic mice.

Results

An analog peptide, CII (256–276, N263, D266), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256–276, N263, D266), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256–276, N263, D266) was effective in down-regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII-immunized mice cultured with CII (256–276, N263, D266) in vitro produced increased amounts of interleukin-4 (IL-4) compared with cells cultured with the wild-type peptide, CII (256–276). Furthermore, CII (256–276, N263, D266) was incapable of preventing arthritis in DR1 IL-4−/− mice (genetically deficient in IL-4).

Conclusion

These data establish that CII (256–276, N263, D266) is a potent suppressor of the DR-mediated immune response to CII. Its effect is mediated, at least in part, by IL-4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis.