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Lecomte_Blanche_89332200_2024-2025.pdf
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- TGF-β1 is an immunosuppressive cytokine that is key for the maintenance of peripheral immune tolerance. It is produced in an inactive (latent) form by almost all cells, and activated only by certain cell types. It has been shown that Tregs, a major source of immunosuppressive TGF-β1, activate this cytokine via the Glycoprotein-A repetitions predominant protein (GARP). Our laboratory previously derived TGF-β1-activating monoclonal antibodies (mAbs) that proved effective against murine graft versus host disease (GvHD). These antibodies have not yet been tested as potential therapeutic agents in autoimmune diseases. The present work involves evaluating the efficacy of TGF-β1-activating mAbs to treat SLE123 mice, which spontaneously develop an autoimmune disease ressembling Systemic Lupus Erythematosus (SLE). Temporality of immune and kidney disease parameters in the SLE123 strain were previously established in the laboratory. To test the therapeutic potential of TGF-β1-activating mAbs, two cohorts of SLE123 and control C57Bl/6 (B6) mice received weekly or bi-weekly injections of an isotype control or a TGF-β1-activating mAb during several months. Half of the mice in Cohort 1 and all mice in Cohort 2 were sacrificed at 8 or 10 months of age, respectively. The other half of Cohort 1 were followed for long-term survival. We assessed immune and kidney disease parameters in the two cohorts. No significant difference in survival and immune or kidney disease parameters were observed between SLE123 mice treated with isotype control or TGF-β1-activating mAbs in either cohort, although glomerulonephritis and IgG deposition have yet to be analysed in Cohort 2. Signs of biological activity of the TGF-β1-activating mAb were observed in SLE123 mice, such as increased expression of TGF-β1 target genes (Serpine1, Col1a2) in the spleen, liver, kidney and skin. However, no overt sign of fibrosis were observed. This observation is important, because exacerbated fibrosis could represent an undesired on-target effet of TGF-β1-activating mAbs used to treat auto- or allo-immune diseases such as GvHD. It will have to be confirmed by completing analyses in Cohort 2.