Interference with CD28, CD80, CD86 or CD152 in Collagen-induced Arthritis. Limited Role of IFN-γ in Anti-B7-mediated Suppression of Disease

doi:10.1006/jaut.2001.0527

Journal of Autoimmunity

Volume 17, Issue 1, August 2001, Pages 39-50

https://doi.org/10.1006/jaut.2001.0527 Get rights and content

Abstract

We have investigated interference with co-stimulation by administering mAbs towards CD28, CD80, CD86, and CD152 in mice immunized for the development of collagen-induced arthritis (CIA). Anti-CD80 and anti-CD86 treatment inhibited disease score and incidence, whereas anti-CD28 treatment led only to a delayed disease onset. Administration of anti-CD152 had no effect. The CII-specific Ab-response was suppressed by the co-stimulatory blockade, with a stronger effect on IgG1 than on IgG2a. The CII-driven T cell proliferation, on the other hand, was not affected. Furthermore, T cells primed in the presence of either anti-B7 or anti-CD28 produced markedly increased amounts of IFN-γ in response to CII. To investigate whether this increase in IFN-γ was related to disease suppression, IFN-γ-deficient mice were immunized with CII, treated with anti-B7 and followed for the development of arthritis. As in the wild-type mice, administration of anti-B7 to IFN-γ-deficient mice led to a reduced disease incidence and severity as well as reduced anti-CII IgG titers. Collectively, these data stress the importance of co-stimulation for the delivery of B cell help rather than for production of Th1 cytokines. We also demonstrate that the enhanced production of IFN-γ observed after B7-blockade is not accountable for the anti-B7 mediated inhibition of CIA.

References (60)

C.H. June et al.
Role of the CD28 receptor in T-cell activation
Immunol. Today
(1990)
M.A. Oosterwegel et al.
CTLA-4 and T cell activation
Curr. Opin. Immunol.
(1999)
D.E. Anderson et al.
The B7-CD28/CTLA-4 costimulatory pathways in autoimmune disease of the central nervous system
Curr. Opin. Immunol.
(1999)
D.J. Lenschow et al.
T cell co-stimulation and in vivo tolerance
Curr. Opin. Immunol.
(1993)
D.J. Lenschow et al.
CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes
Immunity
(1996)
P.J. Perrin et al.
Opposing effects of CTLA4-Ig and anti-CD80 (B7-1) plus anti-CD86 (B7-2) on experimental allergic encephalomyelitis
J. Neuroimmunol.
(1996)
L.M. Webb et al.
Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells
Blood
(1995)
N.L. Harris et al.
The role of B7 costimulation in T-cell immunity
Immunol. Cell Biol.
(1999)
K.D. McCoy et al.
The role of CTLA-4 in the regulation of T cell immune responses
Immunol. Cell Biol.
(1999)
W. Chen et al.
Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells
J. Exp. Med.
(1998)

L.M. Webb et al.

Prevention and amelioration of collagen-induced arthritis by blockade of the CD28 co-stimulatory pathway: requirement for both B7-1 and B7-2

Eur. J. Immunol.

(1996)

D.B. Knoerzer et al.

Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-3-Ig

J. Clin Invest.

(1995)

P.J. Perrin et al.

Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis

J. Immunol.

(1995)

B.K. Finck et al.

Treatment of murine lupus with CTLA4Ig

Science

(1994)

J. Reynolds et al.

CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis

J. Clin Invest.

(2000)

S. Tsuyuki et al.

Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness

J. Exp. Med.

(1997)

S.J. Khoury et al.

CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitic and inhibits Th1 but spares Th2 cytokines in the central nervous system

J. Immunol.

(1995)

Sayegh, M.H. Akalin, E. Hancock, W.W. Russell, M.E. Carpenter, C.B. Linsley, P.S. Turka, L.A. 1995, CD28-B7 blockade...

A. Tang et al.

Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40-ligand

J. Immunol.

(1996)

P.J. Noel et al.

CD28 costimulation prevents cell death during primary T cell activation

J. Immunol.

(1996)

R. Holmdahl et al.

Type II collagen autoimmunity in animals and provocations leading to arthritis

Immunol. Rev.

(1990)

Y. Tada et al.

CD28-deficient mice are highly resistant to collagen-induced arthritis

J. Immunol.

(1999)

A. Corthay et al.

Collagen-induced arthritis development requires alpha beta T cells but not gamma delta T cells: studies with T cell-deficient (TCR mutant) mice

Int. Immunol.

(1999)

P.C. Taylor et al.

The role of the B cells in the adoptive transfer of collagen-induced arthritis from DBA/1 (H-2q) to SCID (H-2d) mice

Eur. J. Immunol.

(1995)

L. Svensson et al.

B cell-deficient mice do not develop type II collagen-induced arthritis (CIA)

Clin Exp. Immunol.

(1998)

V. Malmstrom et al.

Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis

Proc. Natl. Acad. Sci. U.S.A.

(1996)

P.J. Williams et al.

Correlation between IgG anti-type II collagen levels and arthritic severeity in murine arthritis

Autoimmunity

(1998)

N.J. Mauritz et al.

Treatment with gamma-interferon triggers the onset of collagen arthritis in mice

Arthritis Rheum.

(1988)

S.M. Cooper et al.

Suppression of murine collagen-induced arthritis with monoclonal anti-Ia antibodies and augmentation with IFN-gamma

J. Immunol.

(1988)

M.C. Boissier et al.

Biphasic effect of interferon-gamma in murine collagen-induced arthritis

Eur. J. Immunol.

(1995)

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The expression of CD80 is up-regulated in synovial T cells and antigen-presenting cells in rheumatoid arthritis (41, 42). However, administration of anti-CD80 antibody was not therapeutic in CIA (43, 44). The lower molecular weight and the optimal structure in relation to the binding cavity of CD80 probably facilitated greater tissue permeability and blocking efficacy of CD80-CAP1, accounting for its protective effect in CIA.
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^f1: Correspondence to: Mikael Andersson, Fax: +46+46-191105; Tel: +46+46-191262.

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Regular ArticlesInterference with CD28, CD80, CD86 or CD152 in Collagen-induced Arthritis. Limited Role of IFN-γ in Anti-B7-mediated Suppression of Disease

Abstract

Immunol. Today

Curr. Opin. Immunol.

Curr. Opin. Immunol.

Curr. Opin. Immunol.

Immunity

J. Neuroimmunol.

Blood

The role of B7 costimulation in T-cell immunity

Immunol. Cell Biol.

The role of CTLA-4 in the regulation of T cell immune responses

Immunol. Cell Biol.

Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells

J. Exp. Med.

Prevention and amelioration of collagen-induced arthritis by blockade of the CD28 co-stimulatory pathway: requirement for both B7-1 and B7-2

Eur. J. Immunol.

Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-3-Ig

J. Clin Invest.

Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis

J. Immunol.

Treatment of murine lupus with CTLA4Ig

Science

CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis

J. Clin Invest.

Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness

J. Exp. Med.

CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitic and inhibits Th1 but spares Th2 cytokines in the central nervous system

J. Immunol.

Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40-ligand

J. Immunol.

CD28 costimulation prevents cell death during primary T cell activation

J. Immunol.

Type II collagen autoimmunity in animals and provocations leading to arthritis

Immunol. Rev.

CD28-deficient mice are highly resistant to collagen-induced arthritis

J. Immunol.

Collagen-induced arthritis development requires alpha beta T cells but not gamma delta T cells: studies with T cell-deficient (TCR mutant) mice

Int. Immunol.

The role of the B cells in the adoptive transfer of collagen-induced arthritis from DBA/1 (H-2q) to SCID (H-2d) mice

Eur. J. Immunol.

B cell-deficient mice do not develop type II collagen-induced arthritis (CIA)

Clin Exp. Immunol.

Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis

Proc. Natl. Acad. Sci. U.S.A.

Correlation between IgG anti-type II collagen levels and arthritic severeity in murine arthritis

Autoimmunity

Treatment with gamma-interferon triggers the onset of collagen arthritis in mice

Arthritis Rheum.

Suppression of murine collagen-induced arthritis with monoclonal anti-Ia antibodies and augmentation with IFN-gamma

J. Immunol.

Biphasic effect of interferon-gamma in murine collagen-induced arthritis

Eur. J. Immunol.

Regular Articles
Interference with CD28, CD80, CD86 or CD152 in Collagen-induced Arthritis. Limited Role of IFN-γ in Anti-B7-mediated Suppression of Disease