A novel tolerogenic peptide, hCDR1, for the specific treatment of systemic lupus erythematosus

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.

Introduction

Systemic lupus erythematosus (SLE) is a complex disease characterized by the generation of autoantibodies and clinical involvement of multiple organs. T and B cells play a role in the development of SLE. Current therapies for SLE are mainly based on the use of non-specific immunosuppressive drugs and have serious side effects [1]. In spite of intensive efforts, it has been more than 50 years since a new treatment for lupus has been approved. Thus there is an unmet need for novel therapeutic means that will be specific, with improved efficacy and lower toxicity than the currently available therapies for SLE.

As a potential candidate for the specific treatment of SLE patients, we have designed and synthesized a tolerogenic peptide, designated hCDR1 [2], that is based on the sequence of the heavy chain complementarity determining region (CDR)1 of a human monoclonal anti-DNA antibody [3]. hCDR1 was tested for its ability to ameliorate SLE manifestations in spontaneous and induced models of SLE in mice. Administration of hCDR1 (25–50 μg/mouse) subcutaneously [4], once a week for 10 weeks resulted in a significant amelioration of the serological (e.g. reduced autoantibody production) and renal (e.g. diminished proteinuria levels and decreased IgG and complement C3 complex depositions in the glomeruli) manifestations that developed either in the SLE-prone (NZB × NZW)F1 mice, in mice with experimental SLE induced with the anti-DNA autoantibody that bears the 16/6 idiotype (Id) [4], [5] or in severe combined immunodeficient (SCID) mice that were engrafted with peripheral blood mononuclear cells (PBMC) of SLE patients and developed an SLE-like disease [6]. More recently we showed that treatment with hCDR1 down-regulated disease manifestations associated with central nervous system (CNS) lupus, as evidenced by diminished brain pathology (e.g. cell infiltration, immune complex deposits and gliosis) and improved behavior parameters (e.g. anxiety and memory deficit) [7]. Thus, tolerogenic administration of low doses of hCDR1 ameliorated the serological, renal and neurological manifestations of SLE in murine models.