Rheumatoid arthritis (RA) is an
autoimmune disease associated with the recognition of self
proteins secluded in diarthrodial joints. We have previously established that mice transgenic for the human DR genes associated with RA are susceptible to
collagen-induced arthritis (CIA) and we have identified a determinant of
type II collagen (CII(263-270)) that triggers T-cell immune responses in these mice. We have also determined that an analog of CII(263-270) would suppress disease in DR1 transgenic mice. Because the
immunodominant determinant is the same for both DR1 transgenic and DR4 transgenic mice, we attempted to determine whether the analog
peptide that was suppressive in DR1 transgenic mice would also be effective in suppressing CIA in DR4 transgenic mice. We treated DR4 transgenic mice with two analog
peptides of CII that contained substitutions in the core of the
immunodominant determinant: CII(256-276) (F263N, E266D) and CII(256-270) (F263N, E266A). Mice were observed for CIA, and T-cell proliferative responses were determined. Either
peptide administered at the time of immunization with CII significantly downregulated
arthritis. Binding studies demonstrated that replacement of the
phenylalanine residue in position 263 of the CII
peptide with
asparagine significantly decreased the affinity of the
peptide for the DR4 molecule. In contrast, replacement of the
glutamic acid residue in position 266 with
aspartic acid or with
alanine had differing results.
Aspartic acid reduced the affinity (35-fold) whereas
alanine did not. Both
peptides were capable of suppressing CIA. With the use of either
peptide, CII(256-276) (F263N, E266D) or CII(256-270) (F263N, E266A), the modulation of CIA was associated with an increase in T-cell secretion of
IL-4 together with a decrease in IFN-gamma. We have identified two analog
peptides that are potent suppressors of CIA in DR4 transgenic mice. These experiments represent the first description of an analog
peptide of CII recognized by T cells in the context of
HLA-DR4 that can suppress autoimmune
arthritis.