Session Type: Abstract Submissions (ACR)
Background/Purpose: Previous studies indicate that PPAR-γ agonists, including pioglitazone (PIO), down-regulate autoimmune responses and renal inflammation in murine SLE. However, the mechanisms implicated in this process remain unclear. We tested the effect of PIO in human SLE and control PBMCs with regards to gene regulation and various functional assays.
Methods: RNA from PIO-treated or untreated SLE and control PBMCs (4-5/group) was extracted and processed on microarrays (Affymetrix Human U133 Plus 2.0). Confirmation of modulation of specific genes was performed by real-time PCR in lupus and control CD3+, CD4+ or CD8+ T cells isolated by magnetic beads. T cell proliferation was quantified by flow cytrometry with CFSE. Numbers and function of peripheral blood T regulatory cells were quantified by flow cytometry, IL10 synthesis and by suppression assays of effector T cells.
Results: Several T cell-related pathways were highlighted in the analysis of the 1362 transcripts altered by PIO-treated vs. unteated SLE PBMCs. In contrast, only 215 mRNAs were modified in the PIO-treated vs. untreated controls. Resulting network analysis showed Interferon-γ as a major regulatory node, with PIO treatment downregulating various genes implicated in T-cell responses. These suppressive effects of PIO were confirmed in in purified CD4+ and CD8+ T cells by real-time PCR, with significative induction of downregulation of IFN-gamma, CCL4, CCR5, CXCL10 and HES1, among others. PIO downregulated lupus CD4+ T cell proliferation, while it significantly increased numbers and function of lupus T regulatory cells, as assessed by IL-10 synthesis and suppression assays of T effector cells. These effects of PIO were not observed in control T cells.
Conclusion: These results indicate that PPAR-γ agonists selectively modulate T cell function in SLE. Given their beneficial effect in murine lupus, these results support the concept that PIO and related-agents should be further explored as potential therapies in this disease.
C. C. Berthier,
M. J. Kaplan,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-peroxisome-proliferator-activated-receptor-%ce%b3-agonist-pioglitazone-modulates-aberrant-t-cell-responses-in-systemic-lupus-erythematosus/