Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade.
The neonatal FcR (FcRn) plays a critical role in IgG homeostasis by protecting it from a lysosomal degradation pathway. It has been shown that IgG has an abnormally short half-life in FcRn-deficient mice and that FcRn blockade significantly increases the catabolism of serum IgG in mice. Therefore, reduction of serum IgG half-life may have therapeutic benefits in Ab-mediated autoimmune diseases. We have studied the therapeutic effects of an anti-rat FcRn mAb, 1G3, in two rat models of myasthenia gravis, a prototypical Ab-mediated autoimmune disease. Passive experimental autoimmune myasthenia gravis was induced by administration of an anti-acetylcholine receptor (AChR) mAb, and it was shown that treatment with 1G3 resulted in dose-dependent amelioration of the disease symptoms. In addition, the concentration of pathogenic Ab in the serum was reduced significantly. The effect of 1G3 was also studied in an active model of experimental autoimmune myasthenia gravis in which rats were immunized with AChR. Treatment with 1G3 significantly reduced the severity of the disease symptoms as well as the levels of total IgG and anti-AChR IgG relative to untreated animals. These data suggest that FcRn blockade may be an effective way to treat Ab-mediated autoimmune diseases.
Liu
Liming
L
Syntonix Pharmaceuticals, Waltham, MA 02451, USA. lliu@syntnx.com
Garcia
Ana Maria
AM
Santoro
Helen
H
Zhang
Yixia
Y
McDonnell
Kevin
K
Dumont
Jennifer
J
Bitonti
Alan
A
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D001667:Binding, Competitive; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015395:Histocompatibility Antigens Class I; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology; D011961:Receptors, Fc / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; D011961:Receptors, Fc; C100688:Fc receptor, neonatal