Collagen-induced arthritis (CIA) is an experimental model of autoimmune arthritis induced by immunization of susceptible strains of mice with type II collagen (CII). Our recent studies using HLA-DR transgenic (Tg) mice expressing HLA class II molecules associated with susceptibility to rheumatoid arthritis (RA) reveal that DR1 (DRB1*0101) and DR4 (DRB1*0401) can bind and present peptides derived from human (h) CII, and that mice bearing these transgenic DR molecules are susceptible to CIA. The immune response to hCII and arthritis can be down regulated by an analog peptide of CII, A12, CII 256-276 (F263->N, E266->D), when it is co-administered at the time of immunization with hCII. Human CII- sensitized spleen and lymph node cells from DR Tg mice produce increased amounts of IL-4 and IL-10 when cultured with Al2 in comparison to cells cultured with the wild-type CII peptide (CII 256-276). These observations suggest that the suppressive effect of A12 on immune response to CII and CIA in these DR Tg mice is mediated by a shift in the cytokine profile, from that of a Thl to a Th2. However, the mechanism(s) whereby the shift is brought about is not known. Al2 contains two amino acid substitutions as compared to the wild-type CII peptide. The substitutions are of two types, a) residue 263 that participates in peptide binding to the DR molecule, and b) residue 266 that interacts with the TCR. The hypothesis to be tested in this application is that the A12 effect on CIA is mediated through polarization of the specific immune response to a predominant Th2 profile, and that this polarization is caused by changes in the affinity between either DR and peptide or DR/peptide interaction with the TCR leading to altered T cell signaling and, consequently, the production of cytokines. We, therefore, plan to: 1) Identify the structural characteristics of the analog peptide Al2 that mediate its modulation of the immune response to CIIl and CIA in DR Tg mice; 2) Determine whether encoding the Al2 substitutions within the triple helical CII molecule increases the efficacy in inhibiting the autoimmune response in CIA; 3) Determine whether the suppression of CIA produced by A12 administration is dependent on IL-l0 or IL-4 secretion; and 4) Determine the mechanism by which Al2 alters T cell function by analyzing signaling pathways involved in T cell activation. Information gained from these studies will provide important insight for the design of novel therapeutic approaches that may prove beneficial in the treatment of autoimmune arthritis in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043589-06
Application #
6362470
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1995-06-24
Project End
2005-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
6
Fiscal Year
2001
Total Cost
$204,432
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Kimata, Masaru; Cullins, David L; Brown, Monica L et al. (2012) Characterization of inhibitory T cells induced by an analog of type II collagen in an HLA-DR1 humanized mouse model of autoimmune arthritis. Arthritis Res Ther 14:R107
Park, Jeoung-Eun; Cullins, David; Zalduondo, Lillian et al. (2012) Molecular basis for T cell response induced by altered peptide ligand of type II collagen. J Biol Chem 287:19765-74
Brown, Monica; Postlethwaite, Arnold E; Myers, Linda K et al. (2012) Supernatants from culture of type I collagen-stimulated PBMC from patients with cutaneous systemic sclerosis versus localized scleroderma demonstrate suppression of MMP-1 by fibroblasts. Clin Rheumatol 31:973-81
Myers, Linda K; Cullins, David L; Brand, David D et al. (2011) T cells stimulated with an analog peptide of type II collagen require the Fc receptor ýý-chain to secrete interleukin-4 and suppress autoimmune arthritis in mice. Arthritis Rheum 63:2661-70
Tang, Bo; Zhou, Jing; Park, Jeoung-Eun et al. (2009) T cell receptor signaling induced by an analog peptide of type II collagen requires activation of Syk. Clin Immunol 133:145-53
Myers, Linda K; Tang, Bo; Rosioniec, Edward F et al. (2007) An altered peptide ligand of type II collagen suppresses autoimmune arthritis. Crit Rev Immunol 27:345-56
Ye, X J; Tang, B; Ma, Z et al. (2007) The effects of interleukin-18 on rat articular chondrocytes: a study of mRNA expression and protein synthesis of proinflammatory substances. Clin Exp Immunol 149:553-60
Sakurai, Yoshihiko; Brand, David D; Tang, Bo et al. (2006) Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice. Arthritis Res Ther 8:R150
Myers, Linda K; Sakurai, Yoshihiko; Rosloniec, Edward F et al. (2004) An analog peptide that suppresses collagen-induced arthritis. Am J Med Sci 327:212-6
Myers, Linda K; Myllyharju, Johanna; Nokelainen, Minna et al. (2004) Relevance of posttranslational modifications for the arthritogenicity of type II collagen. J Immunol 172:2970-5

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