Abstract
The ICOS (Inducible T cell Co-Stimulator)/B7RP-1 (B7-related protein 1) interaction is critical for the proper activation of a T lymphocyte. In this manuscript we describe a systematic in vivo approach to determine the level of blockade required to impair the generation of a T cell-dependent antibody response. We have developed an overall strategy for correlating drug exposure, target saturation, and efficacy in a biological response that can be generalized for most protein therapeutics. Using this strategy, we determined that low levels of B7RP-1 blockade are still sufficient to inhibit the immune response. These data suggest that contact between the T cell and the antigen-presenting cell during antigen presentation is much more sensitive to inhibition than previously believed and that ICOS/B7RP-1 blockade may be efficacious in the treatment of autoimmune diseases.
MeSH terms
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Aluminum Hydroxide / immunology
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Animals
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Antibodies, Monoclonal / pharmacology
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Antigen-Presenting Cells / immunology
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Antigens, CD19 / metabolism
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B-Lymphocytes / metabolism
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B7-1 Antigen / genetics
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B7-1 Antigen / pharmacology*
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Binding Sites
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CD3 Complex / metabolism
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Cytokines / blood
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Dose-Response Relationship, Drug
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Female
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Fluorescein-5-isothiocyanate / metabolism
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Fluorescent Dyes / metabolism
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Hemocyanins / immunology
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Immune System Phenomena / drug effects*
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Inducible T-Cell Co-Stimulator Ligand
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Mice
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Mice, Inbred BALB C
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Models, Immunological
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Protein Binding
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Recombinant Fusion Proteins / pharmacology
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T-Lymphocytes / metabolism
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Temperature
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Time Factors
Substances
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Antibodies, Monoclonal
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Antigens, CD19
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B7-1 Antigen
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CD3 Complex
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Cytokines
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Fluorescent Dyes
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Inducible T-Cell Co-Stimulator Ligand
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Recombinant Fusion Proteins
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Aluminum Hydroxide
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Hemocyanins
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keyhole-limpet hemocyanin
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Fluorescein-5-isothiocyanate