Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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; Rizzi, M.
Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells.
J AUTOIMMUN. 2019; 101: 145-152.
Doi: 10.1016/j.jaut.2019.04.016
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Thiel Jens
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Abatacept - pharmacology
- Adult - administration & dosage
- Aged - administration & dosage
- Arthritis, Rheumatoid - genetics, immunology, metabolism, pathology
- B-Lymphocytes - drug effects, immunology, metabolism
- B7-1 Antigen - metabolism
- B7-2 Antigen - metabolism
- Female - administration & dosage
- Gene Expression - administration & dosage
- Humans - administration & dosage
- Immunoglobulin G - immunology
- Immunologic Memory - drug effects
- Immunophenotyping - administration & dosage
- Lymphocyte Activation - drug effects, genetics, immunology
- Male - administration & dosage
- Middle Aged - administration & dosage
- Find related publications in this database (Keywords)
- B-lymphocytes
- Abatacept
- CTLA-4
- CD80
- CD86
- Rheumatoid arthritis