Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice

Yoshihiko Sakurai, David Brand, Bo Tang, Edward F. Rosloniec, John Stuart, Andrew Kang, Linda Myers

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 (CII263-270) that triggers T-cell immune responses in these mice. We have also determined that an analog of CII263-270 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: CII256-276 (F263N, E266D) and CII256-270 (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, CII256-276 (F263N, E266D) or CII256-270 (F263N, E266A), the modulation of CIA was associated with an increase in T-cell secretion of IL-4 together with a decrease in IFN-γ. 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.

Original languageEnglish (US)
Article numberR150
JournalArthritis Research and Therapy
Volume8
Issue number5
DOIs
StatePublished - Sep 18 2006

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HLA-DR4 Antigen
Collagen Type II
Transgenic Mice
Arthritis
Experimental Arthritis
Peptides
T-Lymphocytes
Immunodominant Epitopes
Aspartic Acid
Alanine
Rheumatoid Arthritis
HLA-DRB1*04:01 antigen
Asparagine
Phenylalanine
Interleukin-4
Autoimmune Diseases
Glutamic Acid
Immunization
Down-Regulation
Joints

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice. / Sakurai, Yoshihiko; Brand, David; Tang, Bo; Rosloniec, Edward F.; Stuart, John; Kang, Andrew; Myers, Linda.

In: Arthritis Research and Therapy, Vol. 8, No. 5, R150, 18.09.2006.

Research output: Contribution to journalArticle

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