In Vivo Neutralization of TNF-α Promotes Humoral Autoimmunity by Preventing the Induction of CTL

Via, Charles S.; Shustov, Andrei R.; Rus, Violeta; Lang, Thomas; Nguyen, Phuong; Finkelman, Fred D.

doi:10.4049/jimmunol.167.12.6821

Cited by 148 publications

(113 citation statements)

References 43 publications

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“…We have observed striking elevations of serum IFN␥ in acute GVHD mice; however, serum IFN␥ levels in chronic GVHD mice are modestly but significantly increased (40). Studies are currently under way to determine whether these small elevations in IFN␥ play a pathogenic role in disease severity in chronic GVHD mice.…”

Section: Discussionmentioning

confidence: 96%

Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways

Niculescu¹,

Nguyen²,

Niculescu³

et al. 2003

Arthritis & Rheumatism

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Objective. To determine the activation status of two cytoplasmic signaling pathways, phosphatidylinositol 3-kinase (PI 3-kinase) and the mitogen-activated protein kinase (MAPK) family.Methods. We studied the pathogenic CD4؉ T cells that drive disease in the parent-into-F 1 mouse model of lupus-like chronic graft-versus-host disease (GVHD). We determined immunoprecipitated kinase activity for PI 3-kinase and MAPK members ( Results. Compared with negative controls, unfractionated splenocyte kinase activity from chronic GVHD mice was significantly increased for PI 3-kinase and JNK-1, but not for Raf-1, p38 MAPK, or ERK-1. Increased PI 3-kinase and JNK-1 activity was also seen in acute GVHD splenocytes, as was increased Raf-1 and p38 MAPK activity. The pattern of increased PI 3-kinase and JNK-1 activity seen in unfractionated chronic GVHD splenocytes was also seen in isolated donor, but not host, CD4؉ T cells from chronic GVHD mice, indicating that donor CD4؉ T cell signaling activity accounted for at least a portion of the activity observed in unfractionated splenocytes. Increased ERK-1 activity was not seen in either donor or host CD4؉ T cells. This pattern of cytoplasmic signaling pathway in donor CD4؉ T cells was associated with increased T cell receptor membrane signaling activation (Lck and Fyn phosphorylation) and increased transcription activation (phosphorylation of inhibitor of nuclear factor B), confirming the biologic significance of these observations. Conclusion. The pathogenic T cells driving disease in this murine model exhibit activation in the form of spontaneous cytoplasmic signaling pathway activity that can be detected without in vitro restimulation and involves a T cell-specific (PI 3-kinase) and a nonspecific stress/cytokine pathway (JNK-1). These results raise the possibility that a full characterization of the signaling pathways active in pathogenic lupus T cells might lead to new therapeutic targets.

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Section: Discussionmentioning

confidence: 96%

Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways

Niculescu¹,

Nguyen²,

Niculescu³

et al. 2003

Arthritis & Rheumatism

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“…The anti-TNFα treatment blocked the lymphopenia, but induced lupus-like chronic lymphoproliferation and autoantibody production [73]. There was a complete inhibition of anti-host CTL activity, with preferential inhibition of IFN-γ production and of IFN-γ-dependent upregulation of Fas, but not the production of Th2 cytokines, IL-4, IL-6 and IL-10.…”

Section: Mechanism Of Treatment-limiting Adverse Responsesmentioning

confidence: 94%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

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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“…Whereas increasing the CTL activity of donor CD8 + T cells, e.g., treatment of IL-12 (Via et al, 1994) and in vivo ligation of GITR (Kim et al, 2006), changes the type of GVHD from a chronic form to an acute form, its downregulation induces cGVHD instead of aGVHD (Shustov et al, 2000;Via et al, 2001). However, it is not known whether Treg cells can control the development of GVHD by regulating the activity of donor CD8 + T cells.…”

Section: Resultsmentioning

confidence: 99%

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Kim

Kim²,

Choi³

et al. 2006

Exp Mol Med

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In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8 + T cells rapidly fall into anergy to host cells, while donor CD4 + T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8 + T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8 + T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4 + CD25 + regulatory T cells (T reg cells) are critical in maintaining the donor CD8 + T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T reg cells in determining cGVHD versus aGVHD.

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In Vivo Neutralization of TNF-α Promotes Humoral Autoimmunity by Preventing the Induction of CTL

Cited by 148 publications

References 43 publications

Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways

Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways

TNFα blockade in human diseases: Mechanisms and future directions

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

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