Objectives: TNF 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.
Methods: We 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.
Results: In 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.
Conclusion: MTX 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1136/annrheumdis-2018-213403 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Long-term exposure to monoclonal anti-TNF is associated with an increased risk of lymphoma in BAFF-transgenic mice.
Clin Exp Immunol
August 2021
Department of Rheumatology, FHU CARE, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
Article Synopsis
- The study investigates the risk of lymphoma in rheumatoid arthritis patients receiving different types of tumor necrosis factor inhibitors (TNFi), focusing on monoclonal anti-TNF antibodies versus soluble TNF receptors.
- Using a mouse model of autoimmunity, researchers found that prolonged treatment with monoclonal anti-TNF antibodies significantly increased lymphoma risk compared to control groups and those treated with soluble TNF receptors.
- Results indicate lower splenic macrophage infiltration in the monoclonal antibody group, suggesting the need for careful monitoring of lymphoma development in patients with B cell-driven autoimmune diseases undergoing long-term treatment with these antibodies.
Methotrexate and BAFF interaction prevents immunization against TNF inhibitors.
Ann Rheum Dis
October 2018
Rheumatology Department, Université Paris-Sud-CEA-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, Hôpitaux Universitaires Paris-Sud-Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.
Objectives: TNF 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.
Methods: We treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi.
BAFF-driven autoimmunity requires CD19 expression.
J Autoimmun
August 2015
Faculty of Medicine, Nursing and Health Sciences, Department of Immunology, Central Clinical School, Monash University, Commercial Rd, Melbourne 3004, Australia. Electronic address:
B cell activating factor of the tumor necrosis factor family (BAFF or BLyS) is a critical factor for B cell survival and maturation. BAFF-transgenic (BAFF-Tg) mice develop autoimmunity that resembles systemic lupus erythematosus (SLE) in a T cell-independent but MyD88-dependent manner, implicating toll-like receptor (TLR) signaling. The specific B cell subtypes that make pro-inflammatory autoantibodies in BAFF-Tg mice are TLR-activated innate B cells known as marginal zone (MZ) and B1 B cells.
View Article and Find Full Text PDFA role for intrathymic B cells in the generation of natural regulatory T cells.
J Immunol
July 2014
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia; and
B cells inhabit the normal human thymus, suggesting a role in T cell selection. In this study, we report that B cells can modulate thymic production of CD4+ Foxp3+ T cells (regulatory T cells [Tregs]). Mice with transgenic expression of BAFF (BAFF-Tg) harbor increased numbers of Helios+ Foxp3+ thymic Tregs and, similar to some human autoimmune conditions, also exhibit increased numbers of B cells colonizing the thymus.
View Article and Find Full Text PDFBAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis.
PLoS One
December 2011
Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.
Background: BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.
Methodology/principal Findings: Th17 cells were increased in BAFF-Tg B6 (B6.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!