Prevention of lupus nephritis development in NZB/NZW mice by selective blockade of CD28

Abstract : Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoan-tibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4 + T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death-1 (PD-1) and of its ligand programmed death ligand-1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.
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Laetitia Laurent, Awena Le Fur, Rozenn Le Bloas, Mélanie Néel, Caroline Mary, et al.. Prevention of lupus nephritis development in NZB/NZW mice by selective blockade of CD28. European Journal of Immunology, Wiley-VCH Verlag, 2017, 47 (8), pp.1368-1376. ⟨10.1002/eji.201746923⟩. ⟨inserm-02155317⟩

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