The authors undertook the identification of peptides capable of altering the immune response to type II collagen (CII) in the context of HLA-DR, as suppressing the immune response to CII could clarify the role of CII autoimmunity in the pathogenesis of disease. 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. When these analog peptides were used to treat collagen-induced arthritis in DR1 transgenic mice, an analog peptide, CII 256-276 (N, D), was identified that inhibited T-cell responses in vitro. The data from studies with this analog peptide establish that CII 256-276 (N, D) is a potent suppressor of the DR-mediated immune response to CII and that its effect is mediated, at least in part, by interleukin-4. An analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule should have therapeutic significance for autoimmune arthritis.