Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide

Abstract

Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease of unknown etiology that affects many organs, including the kidney. The presence of multiple autoantibodies and other immunological abnormalities point to basic defects in immunoregulatory controls that normally maintain self-tolerance. The deposition on kidney tissue of autoantibodies as immune complexes (ICs) through the interaction with Fc-receptor gamma-chains is thought to trigger an inflammatory response typical of SLE, leading to glomerulonephritis. Using combinatorial chemistry approaches, we have identified a peptide able to bind to immunoglobulins and to interfere with Fcgamma-receptor recognition. Administration of this peptide to MRL/lpr mice, an animal model used to study SLE, resulted in a remarkable enhancement of the survival rate (80%) compared to placebo-treated animals (10%). Consistent with this was a significant reduction of proteinuria, a clinical sign of SLE. Kidney histological examination of treated animals confirmed the preservation of tissue integrity and a remarkable reduction in IC deposition. These results support the role of Fcgamma receptors in SLE pathogenesis and open new avenues for the development of drugs to treat autoimmune disorders.

Role of Oligosaccharide Residues of IgG1-Fc in FcγRIIb Binding

“…On the other hand, aglycosylated anti-CD3 monoclonal antibody has been shown to be a promising candidate for immunosuppressive therapy due to its inability to bind to Fc␥Rs or activate complement (49). Fc␥ fragments are also proven immunosuppressants for the treatment of immune thrombocytopenic purpurea capable of blocking the Fc␥ receptors (50) while peptide inhibitors for the IgG-Fc␥Rs interaction have been developed for modulation of immune response (43,51). Recently we have shown that truncation of the oligosaccharides of humanized anti-major histocompatibility complex class II (L243-IgG1) results in progressive reduction in stimulation of superoxide production through Fc␥RI in a monocyte-like cell line (8).…”

Opsonization of late apoptotic cells by systemic lupus erythematosus autoantibodies inhibits their uptake via an Fcγ receptor–dependent mechanism

“…Fc␥R-blocking antibodies, mouse anti-CD16 IgG clone AT10, and anti-CD64 IgG clone 10.1 were from BD PharMingen (San Diego, CA), and mouse anti-CD32 clone 3G8 was from Serotec (Oxford, UK). IgG-blocking peptide TG19320 (15) was kindly provided by Dr. G. Fassina (Xeptagen, Pozzuoli, Italy).…”

A Small Synthetic Cripto Blocking Peptide Improves Neural Induction, Dopaminergic Differentiation, and Functional Integration of Mouse Embryonic Stem Cells in a Rat Model of Parkinson's Disease

“…In our study we used a reverse screening approach using a defined mechanism/target, the Cripto/ALK-4 receptor complex, and therefore screened a synthetic peptide library to identify a Cripto BP. The choice of a synthetic peptide library was made as peptides are known to be optimal probes to target the extracellular domains of membrane receptors, provided their typical high affinity and selectivity, minimal drug-drug interactions, low accumulation capacity, and low toxicity [31]. Moreover, tetrameric peptides are extremely flexible molecules, have a high-recognition surface, are highly resistant to proteases and can thus be applied in functional assays and in a broad range of applications both in vitro and in vivo.…”

“…To increase the molecular surface, the library was assembled as previously described [31] on a peptide scaffold composed of a poly-lysine core [36]. To facilitate the characterization of the peptide mixtures, and at the same time to expedite the screening procedure, the first residue was arbitrarily fixed.…”

“…For this purpose, we screened a random combinatorial tetrameric tripeptide library built with non-natural amino acids on a multimeric scaffold, which ensured enhanced recognition capabilities deriving from the large recognition surface and the high flexibility of the final compounds [31]. Peptide mixtures composing the library were utilized as competitors of Cripto/ALK-4 interaction in an enzyme-linked immunosorbent assay (ELISA)-based competition assay, following an iterative process.…”