CD3-specific antibodies restore self-tolerance: mechanisms and clinical applications

Chatenoud, Lucienne

doi:10.1016/j.coi.2005.09.011

Cited by 40 publications

(25 citation statements)

References 53 publications

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“…It is possible that depletion regimes that spare regulatory T cells or memory T cells may be particularly successful, because these cells could potentially curb excessive pathological responses of reduced numbers of effector T cells. A remarkably successful strategy that inhibits clinical manifestations of diabetes is the treatment using anti-CD3 Abs, which, similar to the data described here, induce only partial and transient lymphopenia that appears to spare CD25 ϩ CD4 ϩ regulatory T cells (68,69).…”

Section: Discussionsupporting

confidence: 56%

CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia

Bourgeois¹,

Stockinger²

2006

The Journal of Immunology

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Lymphopenia has been associated with autoimmune pathology and it has been suggested that lymphopenia-induced proliferation of naive T cells may be responsible for the development of immune pathology. In this study we demonstrate that lymphopenia-induced proliferation is restricted to conditions of extreme lymphopenia, because neither naive nor memory T cells transferred into T cell-depleted hosts proliferate unless the depletion exceeds 90% of the peripheral repertoire. Memory CD4 T cells as well as regulatory CD4 T cells proved to be relatively resistant to depletion regimes, and both subsets restrict the expansion and phenotypic conversion of naive T cells by an IL-7R-dependent mechanism. It therefore seems unlikely that lymphopenia-induced proliferation of peripheral T cells causes deleterious side effects that result in immune pathology in states of partial and transient lymphopenia.

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Section: Discussionsupporting

confidence: 56%

CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia

Bourgeois¹,

Stockinger²

2006

The Journal of Immunology

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“…Several mechanisms have been proposed for the action of anti-CD3 antibody. Inducing depletion of effector T cells, down regulation of TCR, and immune deviation of the pathogenic T cells toward Th2 cells reviewed in (22). The induction of regulatory T cells by anti-CD3 antibody has also been demonstrated in the animal model for diabetes, in which there was induction of CD4+CD25+ regulatory T cells that differ from the naturally occurring CD4+CD25+ regulatory T cells.…”

Section: Discussionmentioning

confidence: 99%

In vitro induction of regulatory T cells by anti-CD3 antibody in humans

Abraham

Karni

Dembinsky

et al. 2008

Journal of Autoimmunity

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Therapy with anti-CD3 antibody is effective in controlling models of autoimmune diseases and can reverse or prevent rejection of grafts. We studied the in vitro immunomodulatory effect of anti-CD3 treated human T cells. CD4 + T cells were stimulated with plate bound anti-CD3 and cultured for 12 days after which they were cultured with autologous peripheral blood mononuclear cells (PBMCs) and stimulated with soluble anti-CD3. We found that CD4 + T cells that were stimulated with anti-CD3 (T αCD3 ) markedly suppressed the proliferation and cytokine production of autologous PBMCs. These regulatory T cells were not induced by incubation with isotype control (T Control ) antibody or when anti-CD3 was combined with high doses of anti-CD28 (T αCD3/CD28 ). T αCD3 regulatory cells were anergic and produced lower levels of IFN-γ, TNF-α and IL-2, and higher levels of TGF-β than T Control or T αCD3/CD28 .There were no differences in the expression of CD25, CD45RB or CTLA-4 on T αCD3 as compared to T Control or T αCD3/CD28 and CD4 + CD25 − T αCD3 cells were identical to CD4 + CD25 + T αCD3 cells in their in vitro suppressive properties. Recombinant IL-2 in vitro abrogated the suppressive effect of T αCD3 . The suppressive effect was not related to apoptosis, was independent of HLA since T αCD3 also suppressed allogeneic PBMCs, and was not related to soluble factors. Finally, no suppression was observed when non T cells were removed from culture or when cultures were stimulated with plate bound anti-CD3, consistent with the ability of T αCD3 to downregulate CD80 on dendritic cells in co-culture experiments. Thus, we have identified human T cells with strong in vitro regulatory properties induced in vitro by anti-CD3 which appear to act in a non-HLA restricted fashion by affecting antigen presenting cells.

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“…Blockade of co-stimulatory signals through CD4 or CD40L induces peripheral tolerance [72]. CD4 + CD25 + T reg cells can be generated from CD4 + CD25 − T cells in vivo after treatment with non-mito-genic αCD3 F(ab') 2 fragments, suggesting that tolerance and the immune response to antigens are regulated by signal strength [47,49]. Similarly, another study by Ochi et al using oral therapy of αCD3, which induces LAP + [latency-associated peptide (positive)] CD4 + T cells, confirms that TGFβ1-dependent T reg -cell generation is important for preventing autoimmune disease [73].…”

Section: The Role Of Signal Strength In T-cell Activation and Tolerancementioning

confidence: 99%

“…In nonobese diabetic (NOD) mice, which develop spontaneous autoimmune type 1 diabetes, CD4 + CD25 hi T reg cells, but not CD4 + CD25 + cells, exhibit regulatory function and the absence of T reg -cell function in CD4 + CD25 + cells is owing to a lack of TGFβ1 production [2,49]. In these mice, the proportion of TGFβ1-producing T reg cells decreases with age and correlates with disease onset and progression [50].…”

Section: Tgfβ Function In T Reg Cellsmentioning

confidence: 99%

TGFβ1 and Treg cells: alliance for tolerance

Bommireddy

Doetschman

2007

Trends in Molecular Medicine

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Transforming growth factor β1 (TGFβ1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T reg )-cell and effector-cell function and tumorigenesis. Defects in TGFβ1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFβ1 prevents abnormal T-cell activation through the modulation of Ca 2+ -calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T reg cells, its effects are mediated, at least in part, through SMAD signaling. TGFβ1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T h IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFβ1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

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CD3-specific antibodies restore self-tolerance: mechanisms and clinical applications

Cited by 40 publications

References 53 publications

CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia

CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia

In vitro induction of regulatory T cells by anti-CD3 antibody in humans

TGFβ1 and Treg cells: alliance for tolerance

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