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The efficacy of abatacept in reducing synovial T cell activation by CD1c myeloid dendritic cells is overruled by the stimulatory effects of T cell-activating cytokines.
- Source :
-
Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2015 Mar; Vol. 67 (3), pp. 637-44. - Publication Year :
- 2015
-
Abstract
- Objective: To investigate whether the potential of abatacept to inhibit vigorous CD1c myeloid dendritic cell (MDC)-driven activation of naive and memory CD4 T cells is abrogated in the presence of T cell-activating cytokines.<br />Methods: CD4 T cell subsets (naive [Tn], central memory [Tcm], and effector memory [Tem] T cells) were isolated from the peripheral blood (PB) of healthy controls and the PB and synovial fluid (SF) of rheumatoid arthritis (RA) patients. CD4 T cells were cocultured with autologous, thymic stromal lymphopoietin (TSLP)-primed CD1c MDCs in the presence or absence of abatacept (CTLA-4Ig) and/or interleukin-7 (IL-7) or IL-15. Subsequently, T cell proliferation and cytokine production were measured.<br />Results: The percentages of each CD4 T cell subset from the circulation of healthy controls and RA patients were comparable and mainly consisted of Tn and Tcm cells, whereas the SF of RA patients mainly consisted of Tcm and Tem cells. Activation of CD4 T cell subsets by TSLP-primed MDCs from the RA PB was completely blocked by abatacept. Addition of IL-7 or IL-15 to the cocultures strongly increased CD4 T cell activation and overruled the inhibitory capacity of abatacept. IL-7-induced reversal was associated with robust induction of interferon-γ, tumor necrosis factor α, and IL-17 secretion. Similarly, CD4 T cell proliferation induced by TSLP-primed MDCs from the SF of RA patients was strongly blocked by abatacept, but this inhibitory effect was vigorously overruled in the presence of IL-7.<br />Conclusion: These findings indicate that the presence of T cell-activating cytokines such as IL-7 or IL-15 in the joints of RA patients reduces the capacity of abatacept to inhibit MDC-driven CD4 T cell activation. This mechanism may be one explanation for the partial, and sometimes absent, response to abatacept therapy in a subset of patients.<br /> (Copyright © 2015 by the American College of Rheumatology.)
- Subjects :
- Abatacept
Adult
Aged
Arthritis, Rheumatoid pathology
Cell Culture Techniques
Female
Flow Cytometry
Humans
Lymphocyte Activation immunology
Male
Middle Aged
Synovial Fluid cytology
Antigens, CD1 immunology
Arthritis, Rheumatoid immunology
CD4-Positive T-Lymphocytes immunology
Cytokines metabolism
Dendritic Cells immunology
Glycoproteins immunology
Immunoconjugates pharmacology
Immunosuppressive Agents pharmacology
Lymphocyte Activation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2326-5205
- Volume :
- 67
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Arthritis & rheumatology (Hoboken, N.J.)
- Publication Type :
- Academic Journal
- Accession number :
- 25469671
- Full Text :
- https://doi.org/10.1002/art.38982