Lymphoproliferative Disorders with Early Lethality in Mice Deficient in
            <i>Ctla-4</i>

Waterhouse, Paul; Penninger, Josef; Timms, Emma; Wakeham, Andrew; Shahinian, Arda; Lee, Kelvin P.; Thompson, Craig B.; Griesser, Henrik; Mak, Tak W.

doi:10.1126/science.270.5238.985

Cited by 2,548 publications

(1,695 citation statements)

References 33 publications

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“…Treg cell function and maintaining peripheral tolerance [43][44][45]. It is therefore not surprising that the abnormal function of the molecule has been implicated in the aetiology of several autoimmune diseases including vitiligo [46][47][48].…”

Section: Cytotoxic T Lymphocyte Antigen-4mentioning

confidence: 99%

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

100

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Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes.Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.4

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Section: Cytotoxic T Lymphocyte Antigen-4mentioning

confidence: 99%

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

100

View full text Add to dashboard Cite

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“…CTLA-4 has a homologous structure to CD28 and binds to the same ligands, CD80/CD86, as CD28, but with much higher affinity. CTLA-4-deficient ( -/-) mice exhibit massive lymphoproliferative disorder and die at around 5 weeks of age [5,6]. It has been suggested that this lymphoproliferative disorder in CTLA-4 -/-mice is induced by polyclonal activation of peripheral T cells and that it is not due to a defect in the elimination of autoreactive T cells in the thymus [7][8][9][10], providing evidence for the in vivo function of CTLA-4 as a negative regulator of T cell responses [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…CTLA-4-deficient ( -/-) mice exhibit massive lymphoproliferative disorder and die at around 5 weeks of age [5,6]. It has been suggested that this lymphoproliferative disorder in CTLA-4 -/-mice is induced by polyclonal activation of peripheral T cells and that it is not due to a defect in the elimination of autoreactive T cells in the thymus [7][8][9][10], providing evidence for the in vivo function of CTLA-4 as a negative regulator of T cell responses [5,6]. However, the conclusion that CTLA-4 does not influence thymic selection was based mainly on the analyses of thymocyte development in TCR-transgenic (Tg) Â CTLA-4-deficient mice [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

et al. 2005

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Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) induces major inhibitory signals for T cell activation. From analyses of TCR‐transgenic (Tg) CTLA‐4‐deficient mice, it has been believed that CTLA‐4 does not affect thymocyte development. To focus upon the in vivo function of CTLA‐4 in thymocyte development from a different aspect, we have established Tg mice expressing either full‐length CTLA‐4 (FL‐Tg) or a mutant CTLA‐4 lacking the cytoplasmic region (truncated, TR‐Tg), and analyzed thymocyte development. TR‐T cells express much higher CTLA‐4 on the cell surface than FL‐T cells, in which most CTLA‐4 was localized in intracellular vesicles. While CTLA‐4–/– mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA‐4–/– background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double‐positive thymocytes by injection of anti‐CD3 Ab as well as the elimination of minor lymphocyte‐stimulating antigen‐reactive thymocytes were impaired in FL‐Tg mice but not in TR‐Tg mice. Functionally, cross‐linking of CTLA‐4 on thymocytes from FL‐Tg mice, but not from TR‐Tg mice, inhibited proliferation. These results reveal a potential role of CTLA‐4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease.

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“…CTLA-4 is structurally similar to CD28 and binds to CD80/86 with higher affinity than to CD28 (8), playing a crucial role in maintaining peripheral tolerance (9)(10)(11). Abatacept is a soluble fusion protein of the extracellular domain of CTLA-4 and the modified Fc portion of human IgG1 that eliminates complement activation (12,13).…”

mentioning

confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4

Cited by 2,548 publications

References 33 publications

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

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