Abstract
There has been an increase in interest in the use of altered peptides as antigen-specific therapeutic agents in autoimmune diseases. Here we investigated the inhibitory effect and possible mechanism of an altered influenza virus haemagglutinin (HA)-derived peptide in collagen-induced arthritis (CIA). CIA was induced in DBA/1 mice by immunisation with type II collagen (CII). Altered HA308–317, wild-type HA308–317 or irrelevant peptide was administered intranasally beginning from arthritis onset. Clinical and histological scores were assessed, and cytokine levels in the serum or supernatants from splenocytes were determined. The percentages of Th1 and Th2 cells in response to different peptides were analysed by FACS both in vivo and in vitro. Our results showed that intranasal administration of altered HA308–317 peptide significantly ameliorated CIA. The therapeutic effect of altered HA308–317 peptide was associated with a substantial decrease in production of interferon (IFN)-γ, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, anti-CII IgG, IgG1 and IgG2a antibodies, and an markedly increase in production of IL-10 and IL-4 in serum or supernatants from splenocytes treated with altered HA308–317 peptide. The percentage of Th2 (CD4+IL-4+) cells was upregulated significantly by altered HA308–317 peptide with a decreased percentage of Th1 (T helper 1; CD4+INF-γ+) cells both in vivo and in vitro. These findings suggest that altered HA308–317 peptide might be a promising candidate for rheumatoid arthritis (RA) treatment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Edwards JC, Cambridge G . B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol 2006; 6: 394–403.
Monach PA, Benoist C, Mathis D . The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease. Adv Immunol 2004; 82: 217–248.
VanderBorght A, Geusens P, Raus J, Stinissen P . The autoimmune pathogenesis of rheumatoid arthritis: role of autoreactive T cells and new immunotherapies. Semin Arthritis Rheum 2001; 31: 160–175.
Sekine T, Kato T, Masuko-Hongo K, Nakamura H, Yoshino S, Nishioka K et al. Type II collagen is a target antigen of clonally expanded T cell in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 1999; 58: 446–450.
Diab BY, Lambert NC, L'Faqihi FE, Loubet-Lescoulié P, de Préval C, Coppin H . Human collagen II peptide 256–271 preferentially binds to HLA-DR molecules associated with susceptibility to rheumatoid arthritis. Immunogenetics 1999; 49: 36–44.
Dessen A, Lawrence CM, Cupo S, Zaller DM, Wiley DC . X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity 1997; 7: 473–481.
Dayan M, Sthoeger Z, Neiman A, Abarbanel J, Sela M, Mozes E . Immunomodulation by a dual altered peptide ligand of autoreactive responses to the acetylcholine receptor of peripheral blood lymphocytes of patients with myasthenia gravis. Hum Immunol 2004; 65: 571–577.
Kim HJ, Antel JP, Duquette P, Alleva DG, Conlon PJ, Bar-Or A . Persistence of immune responses to altered and native myelin antigens in patients with multiple sclerosis treated with altered peptide ligand. Clin Immunol 2002; 104: 105–114.
Hartemann-Heurtier A, Mars LT, Bercovici N, Desbois S, Cambouris C, Piaggio E et al. An altered self-peptide with superagonist activity blocks a CD8-mediated mouse model of type 1 diabetes. J Immunol 2004; 172: 915–922.
Santambrogio L, Lees MB, Sobel RA . Altered peptide ligand modulation of experimental allergic encephalomyelitis: immune responses within the CNS. J Neuroimmunol 1998; 81: 1–13.
Crowe PD, Qin Y, Conlon PJ, Antel JP . NBI-5788, an altered MBP83–99 peptide, induces a T-helper 2-like immune response in multiple sclerosis patients. Ann Neurol 2000; 48: 758–765.
Xia L, Ru L, Zhanguo L . Altered influenza virus haemagglutinin peptides inhibit T cell responses to type II collagen in rheumatoid arthritis. Ann Rheum Dis 2005; 64: 1790–1791.
Murphy KM, Reiner SL . The lineage decisions of helper T cells. Nat Rev Immunol 2002; 2: 933–944.
Mauri C, Williams RO, Walmsley M, Feldmann M . Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. Eur J Immunol 1996; 26: 1511–1518.
Doncarli A, Stasiuk LM, Fournier C, Abehsira-Amar O . Conversion in vivo from an early dominant Th0/Th1 response to a Th2 phenotype during the development of collagen-induced arthritis. Eur J Immunol 1997; 27: 1451–1458.
Smolen JS, Tohidast-Akrad M, Gal A, Kunaver M, Eberl G, Zenz P et al. The role of T-lymphocytes and cytokines in rheumatoid arthritis. Scand J Rheumatol 1996; 25: 1–4.
Joosten LA, Lubberts E, Durez P, Helsen MM, Jacobs MJ, Goldman M et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. Arthritis Rheum 1997; 40: 249–260.
Walmsley M, Katsikis PD, Abney E, Parry S, Williams RO, Maini RN et al. Interleukin-10 inhibition of the progression of established collagen-induced arthritis. Arthritis Rheum 1996; 39: 495–503.
Horsfall AC, Butler DM, Marinoval L, Warden PJ, Williams RO, Maini RN et al. Suppression of collagen-induced arthritis by continuous administration of interleukin-4. J Immunol 1997; 159: 5687–5696.
Watson WC, Townes AS . Genetic susceptibility to murine collagen II autoimmune arthritis. Proposed relationship to the IgG2 autoantibody subclass response, complement C5, major histocompatibility complex (MHC) and non-MHC loci. J Exp Med 1985; 162: 1878–1891.
O'Garra A, Robinson D . Development and function of T helper 1 cells. Adv Immunol 2004; 83: 133–162.
Kim WU, Lee WK, Ryoo JW, Kim SH, Kim J, Youn J et al. Suppression of collagen-induced arthritis by single administration of poly (lactic-co-glycolic acid) nanoparticles entrapping type II collagen: a novel treatment strategy for induction of oral tolerance. Arthritis Rheum 2002; 46: 1109–1120.
Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H . Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 2003; 48: 2670–2681.
Houssiau FA, Devogelaer JP, van Damme J, de Deuxchaisnes CN, van Snick J . Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988; 31: 784–788.
Tremoulet AH, Albani S . Novel therapies for rheumatoid arthritis. Expert Opin Investig Drugs 2006; 15: 1427–1441.
Koch AE . Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum 2005; 52: 710–721.
Milani M, Ostlie N, Wu H, Wang W, Conti-Fine BM . CD4+ T and B cells cooperate in the immunoregulation of Experimental Autoimmune Myasthenia Gravis. J Neuroimmunol 2006; 179: 152–162.
Berner B, Akça D, Jung T, Muller GA, Reuss-Borst MA . Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol 2000; 27: 1128–1135.
Cremer MA, Rosloniec EF, Kang AH . The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease. J Mol Med 1998; 76: 275–288.
Kim WU, Yoo WH, Park W, Kang YM, Kim SI, Park JH et al. IgG antibodies to type II collagen reflect inflammatory activity in patients with rheumatoid arthritis. J Rheumatol 2000; 27: 575–581.
Mosmann TR, Coffman RL . TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7: 145–173.
Mukherjee P, Wu B, Mayton L, Kim SH, Robbins PD, Wooley PH . TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis. Ann Rheum Dis 2003; 62: 707–714.
Myers LK, Stuart JM, Seyer JM, Kang AH . Identification of an immunosuppressive epitope of type II collagen that confers protection against collagen-induced arthritis. J Exp Med 1989; 170: 1999–2010.
Cher DJ, Mosmann TR . Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol 1987; 138: 3688–3694.
Nandakumar KS, Andrén M, Martinsson P, Bajtner E, Hellström S, Holmdahl R et al. Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcgammaRIIB. Eur J Immunol 2003; 33: 2269–2277.
Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 2006; 442: 997–1002.
Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM et al. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 2006; 310: 850–855.
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 2006; 441: 235–238.
Acknowledgements
This work was supported by grants from the National Major Scientific and Technological Specialized Project (2009ZX09103-746), National Program on Key Basic Research Project (2010CB529100) and National Natural Science Foundation of China (30700751).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sun, J., Jia, Y., Li, R. et al. Altered influenza virus haemagglutinin (HA)-derived peptide is potent therapy for CIA by inducing Th1 to Th2 shift. Cell Mol Immunol 8, 348–358 (2011). https://doi.org/10.1038/cmi.2011.5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cmi.2011.5
Keywords
This article is cited by
-
Blockade of adiponectin receptor 1 signaling inhibits synovial inflammation and alleviates joint damage in collagen-induced arthritis
Clinical Rheumatology (2022)
-
Effect of Saururus chinensis leaves extract on type II collagen-induced arthritis mouse model
BMC Complementary and Alternative Medicine (2019)