The Th2-response in mercuric chloride-induced autoimmunity requires continuing costimulation via CD28.
Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway (BN) rats is a highly polarized polyclonal Th2-driven autoimmune response with increased IgE production, lymphoproliferation, vasculitis and proteinuria. The increase in serum IgE concentration is clearly measurable by day 4 after the first HgCl2 injection and peaks between days 15 and 20. Treatment with CD80 and CD86 antibodies prior to administration of HgCl2 completely suppresses the autoimmune process. To determine whether interruption of CD28 signalling after initial stimulation of the Th2-response would be suppressive, antibody treatment was delayed. BN rats were given 5 doses of HgCl2 subcutaneously on alternate days. CD80 and CD86 antibodies, or an isotype control, were given daily for 3 days and then on alternate days until day 12 commencing either on the day of the first HgCl2 injection (day 0) or on days 4 or 8. Treatment from day 0 reduced serum IgE concentrations to below baseline (median 9.34 microg/ml on day 0 versus 4.6 microg/ml, on day 5, P = 0.03) suggesting that ongoing costimulation via CD28 is required to maintain basal serum IgE production. Delaying treatment until day 4 or day 8 after the first HgCl2 injection resulted in significant inhibition of IgE secretion, lymphoproliferation, and vasculitis, although less markedly than when treatment was commenced on day 0. These data indicate that CD28-mediated costimulation is not only required for the initiation of the Th2-response but is required for maintenance of a maximal response, making this an attractive therapeutic target for antibody-mediated autoimmune diseases.
Department of Renal Medicine, St. George's Hospital Medical School, London, UK. imacphee@sghms.ac.uk
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Macphee
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Turner
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Yagita
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Oliveira
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology*; D015551:Autoimmunity; D018122:B7-1 Antigen / Q000276:immunology / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology*; D003094:Collagen / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007700:Kinetics; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D008627:Mercuric Chloride; D051381:Rats; D011914:Rats, Inbred BN; D018418:Th2 Cells / Q000276:immunology*; D014657:Vasculitis / Q000139:chemically induced / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; D001323:Autoantibodies; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497966:Cd86 protein, rat; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D007073:Immunoglobulin E; D008627:Mercuric Chloride; D003094:Collagen