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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Peres, Raphael Sanches [1] ; Liew, Foo Y. [2, 3] ; Talbot, Jhimmy [1] ; Carregaro, Vanessa [4] ; Oliveira, Rene D. [5] ; Almeida, Sergio L. [5] ; Franca, Rafael F. O. [1] ; Donate, Paula B. [1] ; Pinto, Larissa G. [1] ; Ferreira, Flavia I. S. [6] ; Costa, Diego L. [4] ; Demarque, Daniel P. ; Gouvea, Dayana Rubio [7] ; Lopes, Norberto P. [7] ; Queiroz, Regina Helena C. [6] ; Silva, Joao Santana [4] ; Figueiredo, Florencio [8] ; Alves-Filho, Jose Carlos [1] ; Cunha, Thiago M. [1] ; Ferreira, Sergio H. [1] ; Louzada-Junior, Paulo [5] ; Cunha, Fernando Q. [1]
Total Authors: 22
Affiliation:
[1] Univ Sao Paulo, Dept Pharmacol, Sch Med Ribeirao Preto, Ctr Res Inflammatory Dis, BR-14049900 Ribeirao Preto, SP - Brazil
[2] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow G12 8TA, Lanark - Scotland
[3] Soochow Univ, Sch Biol & Basic Med Sci, Suzhou 215006 - Peoples R China
[4] Univ Sao Paulo, Dept Biochem & Immunol, Sch Med Ribeirao Preto, Ctr Res Inflammatory Dis, BR-14049900 Ribeirao Preto, SP - Brazil
[5] Univ Sao Paulo, Dept Internal Med, Sch Med Ribeirao Preto, Ctr Res Inflammatory Dis, BR-14049900 Ribeirao Preto, SP - Brazil
[6] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Clin Toxicol & Bromatol Anal, BR-14049900 Ribeirao Preto, SP - Brazil
[7] Univ Sao Paulo, Nucleo Pesquisa Prod Nat & Sintet, Fac Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, BR-14049900 Sao Paulo - Brazil
[8] Univ Brasilia, Fac Med, Pathol Lab, BR-70910900 Brasilia, DF - Brazil
Total Affiliations: 8
Document type: Journal article
Source: Proceedings of the National Academy of Sciences of the United States of America; v. 112, n. 8, p. 2509-2514, FEB 24 2015.
Web of Science Citations: 46
Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39(+)CD4(+)CD25(+)FoxP3(+) Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis
Grantee:Fernando de Queiroz Cunha
Support type: Research Projects - Thematic Grants