Abstract

Treatment with a tolerogenic peptide, hCDR1, designed for the specific treatment of systemic lupus erythematosus (SLE) ameliorated the serological and kidney-related clinical manifestations in murine models of induced and spontaneous lupus. Furthermore, hCDR1 reduced brain pathology and improved behavior parameters in mice with central nervous system manifestations. The beneficial effects were associated with a diminished production of pathogenic cytokines (e.g. IFN-γ, IL-10, and IL-1β) and with increased production of the immunosuppressive cytokine, TGF-β. Treatment with hCDR1 up-regulated CD4 and CD8 regulatory T cells (Tregs) that played a key role in the ameliorating effects of hCDR1. Reduction of T cell apoptosis by hCDR1 contributed to the beneficial effects of hCDR. Moreover, treatment with hCDR1 down-regulated B cell maturation and autoreactive B cell survival by diminishing the B cell activating factor (BAFF/BLyS). Finally, hCDR1 suppressed in vivo gene expression of pathogenic cytokines, apoptosis and BLyS and up-regulated immunosuppressive molecules in peripheral blood lymphocytes of SLE patients. The latter was associated with clinical amelioration. Thus, treatment with hCDR1 leads to a cascade of events that culminate in the down-regulation of SLE-associated autoreactive T and B cells and in the clinical amelioration of lupus. hCDR1 is therefore a candidate for the specific treatment of SLE patients.

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