Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

Ehrenstein, Michael R.; Evans, John M.; Singh, Animesh; Moore, Samantha; Warnes, Gary; Isenberg, David; Mauri, Claudia

doi:10.1084/jem.20040165

Cited by 1,131 publications

(994 citation statements)

References 30 publications

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“…Indeed, Treg cells from patients with active RA are defective in their ability to suppress proinflammatory cytokine production by activated Tcells and monocytes in vitro. Anti-TNFα Ab treatment significantly boosts the numbers of circulating Treg cells; the increase in Treg cells correlated with a reduction in CRP [39]. Further, TNFα blockade inhibits the expansion of human CD4 + VLA-1 + effector T cells in vitro, while augmenting the percentage of Treg cells in cultures [40].…”

Section: Effect On Immunoregulationmentioning

confidence: 89%

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: Effect On Immunoregulationmentioning

confidence: 89%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

255

162

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“…These findings argue against an accumulation of T reg to the CNS during relapse and suggest that the functional alteration detectable in CD4 + CD25 high T cells from MS patients is not influenced by disease activity. However, studies with rheumatoid arthritis patients revealed thus far diverging results, showing either stable or reduced numbers of CD25 high regulatory T cells in the peripheral blood [39,40], therefore further studies regarding T reg distribution in active disease are warranted.…”

Section: Discussionmentioning

confidence: 99%

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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Immunoregulatory T cells of CD4 + CD25 + phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4 + CD25 high regulatory T cells (T reg ) to confer suppression of myelin-specific immune responses. Whereas T reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4 + CD25 high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T reg , suggesting that a defective immunoregulation of peripheral T cells mediated by CD4 + CD25 high T lymphocytes promotes CNS autoimmunity in MS.

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“…We and others have demonstrated that Treg isolated from the peripheral blood of patients with RA show a defect in their ability to suppress pro-inflammatory cytokine production [16,17]. There does not appear to be a deficiency in the number of Treg in patients with RA except perhaps in the early phase of disease [18].…”

Section: Cytokine Blockade As a Methods Of Targeting Treg In Patientsmentioning

confidence: 85%

Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis

2008

Self Cite

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Treg play a vital role in the maintenance of tolerance to self antigens, thereby preventing disease through the active suppression of proliferation and pro‐inflammatory cytokine production by autoreactive T cells. Here we discuss strategies aimed at enhancing Treg function in patients with rheumatoid arthritis with the ultimate aim of restoring lasting tolerance but without increasing the risk of infections or cancer. See accompanying commentary:

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Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

Cited by 1,131 publications

References 30 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis

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