Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Peres, Raphael Sanches; Liew, Foo Y.; Talbot, Jhimmy; Carregaro, Vanessa; Oliveira, Renê Donizeti Ribeiro de; Almeida, S L; Franca, Rafael Freitas Oliveira; Donate, Paula B.; Pinto, Lidiane de Castro; Ferreira, Flávia Isaura Santi; Costa, Diego L.; Demarque, Daniel P.; Gouvea, Dayana Rubio; Lopes, Norberto P.; Queiróz, Regina Helena Costa; Silva, João; Figueiredo, Florêncio; Alves-Filho, José C.; Cunha, Thiago Mattar; Ferreira, Séérgio H.; Louzada‐Júnior, Paulo; Cunha, Fernando Q.

doi:10.1073/pnas.1424792112

Cited by 116 publications

(111 citation statements)

References 35 publications

(34 reference statements)

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“…CD73 is required for low-dose MTX-induced immunomodulatory effect observed in the air pouch model 5 6. CD39, the directly upstream ectoenzyme of CD73, has also been shown to influence clinical response to MTX in patients with RA 25. The interaction between MTX and BAFF can be explained, at least partly, by the increase of CD73 expression on B cells from BAFFtg mice.…”

Section: Discussionmentioning

confidence: 99%

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Bitoun

Nocturne

et al. 2018

Ann Rheum Dis

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ObjectivesTNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation.MethodsWe treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs).We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation.ResultsIn BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy.ConclusionMTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.

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Section: Discussionmentioning

confidence: 99%

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Bitoun

Nocturne

et al. 2018

Ann Rheum Dis

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“…The regulatory effects of CD39 + Tregs on experimental RA and RA patients subjected to anti-IL-6 receptor (IL-6R) treatment were also been shown by flow cytometric analysis of peripheral blood. 77 Low peripheral expression levels of CD39 have also been proposed as biomarkers for RA in patients 78 , and CD39-expressing Tr1 cells proposed as potential therapy against arthritis. 79 In patients suffering from inflammatory bowel disease, peripheral Th17 cells expressing CD39 had enhanced in vitro immunosuppressive effects.…”

Section: Murine Cd39 Expressing T Cells As Enhanced Immunomodulation mentioning

confidence: 99%

The influence of gut-derived CD39 regulatory T cells in CNS demyelinating disease

Ochoa‐Repáraz

Kasper

2017

Translational Research

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There is considerable interest in trying to understand the importance of the gut microbiome in human diseases. The association between dysbiosis, an altered microbial composition, as related to human disease is being explored in the context of different autoimmune conditions, including multiple sclerosis (MS). Recent studies suggest that MS affects the composition of the gut microbiota by altering the relative abundances of specific bacteria and archaea species. Remarkably, some of the bacterial species shown reduced in the gut of MS patients are known to promote immunosuppressive regulatory T cells (Tregs). In MS, the function of a phenotype of Tregs that express CD39, an ectoenzyme involved in the catabolism of ATP as immumomodulatory cells, appears to be reduced. In this review we discuss the involvement of the gut microbiota in the regulation of experimental models of CNS inflammatory demyelination and review the evidence that link the gut microbiome with multiple sclerosis. Further, we hypothesize that the gut microbiome is an essential organ for the control of tolerance in multiple sclerosis patients and a potential source for safer novel therapeutics.

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“…However, a significant percentage of rheumatoid arthritis patients are resistant to MTX treatment. Peres et al [26] found that MTX unresponsiveness in rheumatoid arthritis patients was associated with low expression of CD39 on Treg cells and the deceased suppressive activity of Treg cells through reduced adenosine production. These data suggested that low expression of CD39 on Treg cells could be a biomarker for identifying MTX-resistance rheumatoid arthritis patients.…”

Section: Adenosine Pathway Changes In Human Autoimmune Diseasesmentioning

confidence: 99%

The role of adenosinergic pathway in human autoimmune diseases

2016

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Autoimmune diseases are characterized by the abnormal immune response against self-tissue, which are caused by the failure of nature immune homeostasis. Nature immune homeostasis represents the normal state of appropriate immune response to nonself-antigen and unresponsiveness to self-antigens. In normal situation, immune homeostasis is regulated by immunosuppressive signal and immunostimulating signal together. Accumulating data have demonstrated that the adenosinergic pathway played key roles in immune suppression and shield body from an excessive inflammatory response. The deficiency of adenosinergic pathway results in the imbalance between the pro- and anti-inflammatory activities. Thus, researchers pay much attention to the role of adenosinergic pathway in autoimmune diseases development. To date, accumulating data have suggested an important role of adenosinergic pathway-related molecules (i.e., CD39, CD73, ADA, adenosine receptors, etc.) in many types of human autoimmune diseases. More importantly, these findings have presented potential value of adenosinergic pathway analysis to be used for autoimmune diseases diagnosis, monitoring and treatment. In this review, we will provide a comprehensive description of the role of adenosinergic pathway in human autoimmune diseases.

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Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Cited by 116 publications

References 35 publications

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

The influence of gut-derived CD39 regulatory T cells in CNS demyelinating disease

The role of adenosinergic pathway in human autoimmune diseases

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