Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis.

Williams, Richard O.; Mason, Lesley; Feldmann, Marc; Maini, R. N.

doi:10.1073/pnas.91.7.2762

Cited by 173 publications

(95 citation statements)

References 31 publications

(28 reference statements)

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“…injections of TN3-19.12, a hamster IgG1 mAb to murine TNFα/β, into CIA mice either before or after the onset of clinical arthritis significantly reduced paw swelling and histological severity of arthritis without reducing the incidence of arthritis or the level of the circulating antitype II collagen IgG [57]. Co-administration of anti-CD4 and a suboptimal dose of anti-TNFα/β to the CIA mice not only reduced paw-swelling and prevented limb involvement and joint erosion, it was also effective in preventing an Ab response to the hamster anti-TNF Abs [58]. These findings may have implications for a long-term therapy in human disease, as they suggest a possibility for treatment that may help eliminate the adverse outcome of autoimmunity following anti-TNFα treatment.…”

Section: Mechanistic Lessons From Animal Modelsmentioning

confidence: 94%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

255

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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Section: Mechanistic Lessons From Animal Modelsmentioning

confidence: 94%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

255

162

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“…Pro-inflammatory cytokines play important roles in this process, as evidenced by the clinical success of cytokine blockade therapies [1,2]. Similar to human RA, various pro-inflammatory cytokines including TNF-a and IL-1b are involved in the pathogenesis of collagen-induced arthritis (CIA), a rodent model of human RA [3][4][5]. The development of CIA depends on both cellular and humoral immune responses to type II collagen (CII) that activate inflammatory cytokine cascades [3,6].…”

Section: Introductionmentioning

confidence: 99%

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

et al. 2007

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IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4 + T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4 + T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4 + T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4 + T cells. IntroductionRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissues in multiple joints, which results in destruction of bone and cartilage. Pro-inflammatory cytokines play important roles in this process, as evidenced by the clinical success of cytokine blockade therapies [1,2]. Similar to human RA, various pro-inflammatory cytokines including TNF-a and IL-1b are involved in the pathogenesis of collagen-induced arthritis (CIA), a rodent model of human RA [3][4][5]. The development of CIA depends on both cellular and humoral immune responses to type II collagen (CII) that activate inflammatory cytokine cascades [3,6]. The Th1 response was believed to be essential for the development of the disease [3]. However, recent studies have indicated a critical role of IL-17 in the pathogenesis of autoimmune disease models such as CIA [7,8].IL-17 is a pro-inflammatory cytokine produced mainly by memory CD4 + T cells that stimulates synoviocytes or macrophages to induce various cytokines such as TNF-a and IL-1 [9][10][11]. Lubberts et al. [7] have demonstrated that treatment of DBA1 mice with neutralizing anti-IL-17 Ab shortly after the onset suppressed the development of the CIA, suggesting a critical role of IL-17 at the effector phase. In addition, Nakae et al. [8] have reported, using IL-17-deficient mice with C57BL/6 Â 129 background, that IL-17 was also involved in CIA at the induction phase. IL-17 expression is strongly induced in memory T cells by IL-23, a member of the IL-12 family of cytokines, via signaling through its receptor composed of . Recently, it was demonstrated that IL-23 but not IL-12 is indispensable for the development of CIA, indicating that an IL-17-producing CD4 + T cell response, but not the "classical" Th1 response, is essential for the disease [13,14]. IL-15, a member of the four-helix bundle cytokine family, stimulates macrophages/dendritic cells, natural killer (NK) cells, NKT cells, mucosal...

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“…For that reason, animal experiments are required to optimize immunomodulatory protocols and to identify the mechanism of operation of an anti-CD4 MoAb. On the other hand, several studies have been performed on collagen-induced arthritis (CIA) in mice using anti-CD4 MoAbs [15][16][17], and although these treatments were found to prevent the induction of CIA, they were ineffective in ameliorating established arthritis.…”

Section: Introductionmentioning

confidence: 99%

Treatment with an anti-CD4 monoclonal antibody strongly ameliorates established rat adjuvant arthritis

Pelegrí

Morante

Castellote

et al. 1996

Clinical and Experimental Immunology

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SUMMARYSome experimental arthritic diseases can be prevented by treatment with anti-CD4 MoAbs. Trials with ongoing disease have not been successful so far. The aim of this study was to ascertain whether W3/25 could reverse adjuvant arthritis (AA), when beginning treatment on day 14, i.e. when the disease was established. Moreover, one group of animals treated with the anti-CD4 MoAb received OX8 MoAb at the same time, thus depleting CD8 cells from circulation. During treatment with W3/25, a strong amelioration of inflammatory signals was observed, as assessed by means of paw volume increase and arthritic score. However, when treatment stopped, a rebound to arthritis signals occurred. The parallel depletion of CD8 cells did not modify these effects, thus the combined treatment W3/25 OX8 gave the same amelioration as treatment with W3/25 alone. These findings indicate that CD4 cells play an important role in perpetuating rat AA. Moreover, CD8 cells do not seem to have a regulatory role in the CD4 cells responsible for the inflammatory response.

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Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis.

Abstract: Anti-CD4 ttmet is reported to prevent

Cited by 173 publications

References 31 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

Treatment with an anti-CD4 monoclonal antibody strongly ameliorates established rat adjuvant arthritis

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Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis.

Abstract: Anti-CD4 ttmet is reported to prevent

Cited by 173 publications

References 31 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4+ T cell response to produce IL‐17

Treatment with an anti-CD4 monoclonal antibody strongly ameliorates established rat adjuvant arthritis

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IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17