CTLA-4 and autoimmunity: New insights into the dual regulator of tolerance

Romo-Tena, Jorge; Gómez‐Martín, Diana; Alcocer‐Varela, Jorge

doi:10.1016/j.autrev.2013.07.002

Cited by 116 publications

(75 citation statements)

References 55 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

103

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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

103

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“…59 CLTA4, a critical immunoregulatory gene, helps maintain tolerance to self-antigens by elevating the T-cell activation threshold. 60 An anti-CTLA4 antibody approved to treat melanoma, ipilimumab, functions in part by releasing this immunity checkpoint inhibitor, allowing the patient's cytotoxic T lymphocytes to mount a more robust antitumor immune response-a response that could also be used in sarcoma therapy. 61 Moreover, three of the other sarcoma subtypes in our study also contained a known drug target in their top 10 differentially upregulated gene lists: PLA2G2A, upregulated in our fibromatosis samples, is a member of the prostaglandin family and can be downregulated by indomethacin, a nonsteroidal anti-inflammatory drug that targets COX1 and COX2, which are involved in prostaglandin synthesis.…”

Section: Therapeutic Targets In Human Soft Tissue Tumors Ae Sarver Et Almentioning

confidence: 99%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

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“…Deguelin suppression of NF-κB transcription of pro-inflammatory genes may also explain reduced pro-inflammatory cytokine production following SEB exposure. Additional cellular targets influencing the PI3K/Akt pathway include inhibitors of IL-2 receptor signaling, such as basiliximab, daclizumab and inhibitors of CD28 signaling, such as abatacept [55]. Further research will be required to demonstrate the efficacy of these agents in preventing superantigen toxicity in vivo.…”

Section: Discussionmentioning

confidence: 99%

The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

Whitfield¹,

Risdall²,

Griffiths³

et al. 2017

ABB

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Staphylococcal Enterotoxin B (SEB) is considered a potential biological weapon. It is toxic by both inhalation and ingestion. Effects of ingestion include fever, vomiting and diarrhoea, while inhalation may additionally result in chest pain, dyspnoea, pulmonary oedema and respiratory failure. Severe exposure may be fatal and treatment relies on symptomatic support. At a cellular level, SEB up-regulates T-cell proliferation leading to a pathological inflammatory response. Deguelin, a rotenoid isolated from the African plant Mundulea sericea (Leguminosae), has been shown to reduce cellular proliferation by inhibiting the phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway. Using isolated murine splenocytes, we have demonstrated that treatment with deguelin reduces SEB inducing T cell proliferation by 60%. Deguelin treatment also decreased IL-2 and CCL2 secretion by splenocytes exposed to SEB. We demonstrate that targeting cellular proliferation can significantly reduce inflammation after SEB exposure and suggest that antiproliferatives may have a role as potential generic medical counter measures if superantigens are used as biological weapons.

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CTLA-4 and autoimmunity: New insights into the dual regulator of tolerance

Cited by 116 publications

References 55 publications

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

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