1. Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells.
- Author
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Lorenzetti R, Janowska I, Smulski CR, Frede N, Henneberger N, Walter L, Schleyer MT, Hüppe JM, Staniek J, Salzer U, Venhoff A, Troilo A, Voll RE, Venhoff N, Thiel J, and Rizzi M
- Subjects
- Adult, Aged, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid metabolism, Arthritis, Rheumatoid pathology, B-Lymphocytes drug effects, Female, Humans, Immunoglobulin G immunology, Immunophenotyping, Lymphocyte Activation drug effects, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Male, Middle Aged, Abatacept pharmacology, B-Lymphocytes immunology, B-Lymphocytes metabolism, B7-1 Antigen metabolism, B7-2 Antigen metabolism, Gene Expression, Immunologic Memory drug effects
- Abstract
Background: Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits T-cell activation and is expressed on T-regulatory cells. Human CTLA-4 deficiency results in severe immune dysregulation. Abatacept (CTLA-4 Ig) is approved for the treatment of rheumatoid arthritis (RA) and its mechanism of action is attributed to effects on T-cells. It is known that CTLA-4 modulates the expression of its ligands CD80 and CD86 on antigen presenting cells (APC) by transendocytosis. As B-cells express CD80/CD86 and function as APC, we hypothesize that B-cells are a direct target of abatacept., Objectives: To investigate direct effects of abatacept on human B-lymphocytes in vitro and in RA patients., Methods: The effect of abatacept on healthy donor B-cells' phenotype, activation and CD80/CD86 expression was studied in vitro. Nine abatacept-treated RA patients were studied. Seven of these were followed up to 24 months, and two up to 12 months only and treatment response, immunoglobulins, ACPA, RF concentrations, B-cell phenotype and ACPA-specific switched memory B-cell frequency were assessed., Results: B-cell development was unaffected by abatacept. Abatacept treatment resulted in a dose-dependent decrease of CD80/CD86 expression on B-cells in vitro, which was due to dynamin-dependent internalization. RA patients treated with abatacept showed a progressive decrease in plasmablasts and serum IgG. While ACPA-titers only moderately declined, the frequency of ACPA-specific switched memory B-cells significantly decreased., Conclusions: Abatacept directly targets B-cells by reducing CD80/CD86 expression. Impairment of antigen presentation and T-cell activation may result in altered B-cell selection, providing a new therapeutic mechanism and a base for abatacept use in B-cell mediated autoimmunity., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2019
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