Peptide-induced suppression of collagen-induced arthritis in HLA-DR1 transgenic mice

Linda Myers, Yoshihiko Sakurai, B. Tang, Xiaowen He, Edward F. Rosloniec, John M. Stuart, Andrew Kang

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Objective. To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA-DR. Methods. Immunizing mice transgenic for the human HLA-DRB1*0101 immune response gene with CII elicits an arthritis (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263-270), recognized by T cells in the context of DR1. 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. These peptides were used to treat CIA in DR1 transgenic mice. Results. An analog peptide, CII (256-276, N263, D266), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256-276, N263, D266), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256-276, N263, D266) was effective in down-regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII-immunized mice cultured with CII (256-276, N263, D266) in vitro produced increased amounts of interleukin-4 (IL-4) compared with cells cultured with the wild-type peptide, CII (256-276). Furthermore, CII (256-276, N263, D266) was incapable of preventing arthritis in DR1 IL-4-/- mice (genetically deficient in IL-4). Conclusion. These data establish that CII (256-276, N263, D266) is a potent suppressor of the DR-mediated immune response to CII. Its effect is mediated, at least in part, by IL-4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis.

Original languageEnglish (US)
Pages (from-to)3369-3377
Number of pages9
JournalArthritis and Rheumatism
Volume46
Issue number12
DOIs
StatePublished - Dec 1 2002

Fingerprint

HLA-DR1 Antigen
Experimental Arthritis
Transgenic Mice
Arthritis
Peptides
Interleukin-4
T-Lymphocytes
HLA-DRB1 Chains
Immunodominant Epitopes
Collagen Type II
HLA-DR Antigens
Major Histocompatibility Complex
Antibody Formation
Cultured Cells
Immunization
Rheumatoid Arthritis
Spleen
Lymph Nodes
Incidence

All Science Journal Classification (ASJC) codes

  • Immunology
  • Rheumatology

Cite this

Peptide-induced suppression of collagen-induced arthritis in HLA-DR1 transgenic mice. / Myers, Linda; Sakurai, Yoshihiko; Tang, B.; He, Xiaowen; Rosloniec, Edward F.; Stuart, John M.; Kang, Andrew.

In: Arthritis and Rheumatism, Vol. 46, No. 12, 01.12.2002, p. 3369-3377.

Research output: Contribution to journalArticle

Myers, Linda ; Sakurai, Yoshihiko ; Tang, B. ; He, Xiaowen ; Rosloniec, Edward F. ; Stuart, John M. ; Kang, Andrew. / Peptide-induced suppression of collagen-induced arthritis in HLA-DR1 transgenic mice. In: Arthritis and Rheumatism. 2002 ; Vol. 46, No. 12. pp. 3369-3377.
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abstract = "Objective. To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA-DR. Methods. Immunizing mice transgenic for the human HLA-DRB1*0101 immune response gene with CII elicits an arthritis (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263-270), recognized by T cells in the context of DR1. 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. These peptides were used to treat CIA in DR1 transgenic mice. Results. An analog peptide, CII (256-276, N263, D266), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256-276, N263, D266), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256-276, N263, D266) was effective in down-regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII-immunized mice cultured with CII (256-276, N263, D266) in vitro produced increased amounts of interleukin-4 (IL-4) compared with cells cultured with the wild-type peptide, CII (256-276). Furthermore, CII (256-276, N263, D266) was incapable of preventing arthritis in DR1 IL-4-/- mice (genetically deficient in IL-4). Conclusion. These data establish that CII (256-276, N263, D266) is a potent suppressor of the DR-mediated immune response to CII. Its effect is mediated, at least in part, by IL-4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis.",
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AU - Sakurai, Yoshihiko

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AU - Rosloniec, Edward F.

AU - Stuart, John M.

AU - Kang, Andrew

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AB - Objective. To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA-DR. Methods. Immunizing mice transgenic for the human HLA-DRB1*0101 immune response gene with CII elicits an arthritis (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263-270), recognized by T cells in the context of DR1. 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. These peptides were used to treat CIA in DR1 transgenic mice. Results. An analog peptide, CII (256-276, N263, D266), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256-276, N263, D266), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256-276, N263, D266) was effective in down-regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII-immunized mice cultured with CII (256-276, N263, D266) in vitro produced increased amounts of interleukin-4 (IL-4) compared with cells cultured with the wild-type peptide, CII (256-276). Furthermore, CII (256-276, N263, D266) was incapable of preventing arthritis in DR1 IL-4-/- mice (genetically deficient in IL-4). Conclusion. These data establish that CII (256-276, N263, D266) is a potent suppressor of the DR-mediated immune response to CII. Its effect is mediated, at least in part, by IL-4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis.

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