Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways.
Murine lupus in NZB/NZW F1 (B/W) mice can be retarded by sustained administration of CTLA4Ig and by brief treatment early in life with mAb that block CD40/gp39 interactions. We sought to determine whether brief therapy with CTLA4Ig could provide sustained benefit in B/W mice and whether a synergistic effect could be derived by blockade of both the B7/CD28 and the CD40/gp39 pathways. We found that a short course of CTLA4Ig at the onset of disease produced only short-term benefit. However, when CTLA4Ig was combined with anti-gp39, there was long-lasting inhibition of autoantibody production and renal disease. Ten months after the 2-wk course of therapy, 70% of these mice were alive, compared with only 18% and 0% of those that received only anti-gp39 or CTLA4Ig, respectively. These findings demonstrate that brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways can produce benefit that lasts long after treatment has been discontinued.
Daikh
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Department of Medicine, Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA. daikh@itsa.ucsf.edu
Finck
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Linsley
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Hollenbaugh
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Wofsy
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D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D004357:Drug Synergism; D005260:Female; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D008181:Lupus Nephritis / Q000209:etiology* / Q000276:immunology* / Q000517:prevention & control; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008814:Mice, Inbred NZB; D013997:Time Factors
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D000069594:Abatacept