Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells

A novel function for an ancient protein

Rebecca J. Brownlie, Linda Myers, Paul H. Wooley, Valerie M. Corrigall, Mark D. Bodman-Smith, Gabriel S. Panayi, Stephen J. Thompson

Research output: Contribution to journalArticle

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Abstract

Objective. Following the demonstration that the stress protein, BiP, prevented induction of collagen-induced arthritis (CIA) in HLA- DRB*0101+/+ (HLA-DR1+/+) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA-DR1+/+ and DBA/1 mice. Methods. BiP was administered either subcutaneously or intravenously to DBA/1, HLA-DR1+/+, or interleukin-4 (IL-4)-knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti-CII antibodies were measured by enzyme-linked immunosorbent assay. Disease progression was scored using a visual analog scale. Results. BiP was successful in suppressing established CIA in HLA-DR1+/+ and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP-treated mice. T cells from BiP-immunized mice produced Th2 cytokines, in particular, IL-4. Treatment with BiP was also shown to increase the production of CII-specific IL-5, IL-10, and interferon-γ at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP-specific cells at the time of CIA induction in HLA-BR1+/+ mice or by transferring BiP-specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL-4-/-, HLA-DR1 +/+ mice. Conclusion. These novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL-4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.

Original languageEnglish (US)
Pages (from-to)854-863
Number of pages10
JournalArthritis and rheumatism
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2006

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Experimental Arthritis
Regulatory T-Lymphocytes
Heat-Shock Proteins
Interleukin-4
Dichlororibofuranosylbenzimidazole
Inbred DBA Mouse
Proteins
Therapeutics
HLA-DR1 Antigen
Cytokines
Collagen Type II
Adoptive Transfer
Interleukin-5
Proxy
Serum
Visual Analog Scale
Knockout Mice
Interleukin-10
Interferons
Arthritis

All Science Journal Classification (ASJC) codes

  • Immunology
  • Rheumatology

Cite this

Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells : A novel function for an ancient protein. / Brownlie, Rebecca J.; Myers, Linda; Wooley, Paul H.; Corrigall, Valerie M.; Bodman-Smith, Mark D.; Panayi, Gabriel S.; Thompson, Stephen J.

In: Arthritis and rheumatism, Vol. 54, No. 3, 01.03.2006, p. 854-863.

Research output: Contribution to journalArticle

Brownlie, Rebecca J. ; Myers, Linda ; Wooley, Paul H. ; Corrigall, Valerie M. ; Bodman-Smith, Mark D. ; Panayi, Gabriel S. ; Thompson, Stephen J. / Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells : A novel function for an ancient protein. In: Arthritis and rheumatism. 2006 ; Vol. 54, No. 3. pp. 854-863.
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abstract = "Objective. Following the demonstration that the stress protein, BiP, prevented induction of collagen-induced arthritis (CIA) in HLA- DRB*0101+/+ (HLA-DR1+/+) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA-DR1+/+ and DBA/1 mice. Methods. BiP was administered either subcutaneously or intravenously to DBA/1, HLA-DR1+/+, or interleukin-4 (IL-4)-knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti-CII antibodies were measured by enzyme-linked immunosorbent assay. Disease progression was scored using a visual analog scale. Results. BiP was successful in suppressing established CIA in HLA-DR1+/+ and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP-treated mice. T cells from BiP-immunized mice produced Th2 cytokines, in particular, IL-4. Treatment with BiP was also shown to increase the production of CII-specific IL-5, IL-10, and interferon-γ at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP-specific cells at the time of CIA induction in HLA-BR1+/+ mice or by transferring BiP-specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL-4-/-, HLA-DR1 +/+ mice. Conclusion. These novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL-4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.",
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AU - Myers, Linda

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AU - Corrigall, Valerie M.

AU - Bodman-Smith, Mark D.

AU - Panayi, Gabriel S.

AU - Thompson, Stephen J.

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AB - Objective. Following the demonstration that the stress protein, BiP, prevented induction of collagen-induced arthritis (CIA) in HLA- DRB*0101+/+ (HLA-DR1+/+) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA-DR1+/+ and DBA/1 mice. Methods. BiP was administered either subcutaneously or intravenously to DBA/1, HLA-DR1+/+, or interleukin-4 (IL-4)-knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti-CII antibodies were measured by enzyme-linked immunosorbent assay. Disease progression was scored using a visual analog scale. Results. BiP was successful in suppressing established CIA in HLA-DR1+/+ and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP-treated mice. T cells from BiP-immunized mice produced Th2 cytokines, in particular, IL-4. Treatment with BiP was also shown to increase the production of CII-specific IL-5, IL-10, and interferon-γ at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP-specific cells at the time of CIA induction in HLA-BR1+/+ mice or by transferring BiP-specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL-4-/-, HLA-DR1 +/+ mice. Conclusion. These novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL-4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.

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