Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide.
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.
Marino
M
M
TECNOGEN S.C.p.A. Biopharmaceuticals, 81015 Piana di Monte Verna (CE), Italy.
Ruvo
M
M
De Falco
S
S
Fassina
G
G
D000367:Age Factors; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D019921:Biotinylation; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology; D007136:Immunoglobulins / Q000378:metabolism*; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000517:prevention & control* / Q000628:therapy; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D011961:Receptors, Fc / Q000378:metabolism; D020298:U937 Cells
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D007136:Immunoglobulins; D009842:Oligopeptides; D010455:Peptides; D011961:Receptors, Fc; C413702:TG 19320