Abstract
The development of a maturing T-cell-mediated immune response was characterized in Parkinson's disease subjects receiving recombinant human glial-derived neurotrophic factor (r-metHuGDNF) via continuous bilateral intraputaminal infusion. Eighteen of 34 subjects tested positive for anti-r-metHuGDNF-binding antibodies. Four subjects developed neutralizing activity, three of which demonstrated classic immunoglobulin class switching from IgM to IgG. An increase of anti-r-metHuGDNF IgG-binding antibodies correlated with the development of neutralizing activity. All serum samples from two subjects with neutralizing activity were characterized for IgG subclasses. These data revealed an initial anti-r-metHuGDNF IgG population where IgG1 >> IgG2 >> IgG4, and IgG3 concentrations were negligible. However, continued antigenic stimulation resulted in concentration changes where IgG4 > IgG1> IgG2, indicating a mature immune response. In addition, using in silico techniques, two immunodominant MHC class II T-cell epitopes were predicted for the native GDNF sequence. These data demonstrate development of a mature T-cell-mediated immune response in these subjects.
Publication types
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Clinical Trial, Phase II
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Multicenter Study
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Randomized Controlled Trial
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Validation Study
MeSH terms
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Animals
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Binding Sites, Antibody
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Cell Differentiation / immunology*
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Clone Cells
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Double-Blind Method
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Glial Cell Line-Derived Neurotrophic Factor / administration & dosage*
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Glial Cell Line-Derived Neurotrophic Factor / genetics
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Glial Cell Line-Derived Neurotrophic Factor / immunology
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Glial Cell Line-Derived Neurotrophic Factor / metabolism
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Glial Cell Line-Derived Neurotrophic Factor / therapeutic use*
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Humans
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Immunoglobulin Class Switching / immunology
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Immunoglobulin G / biosynthesis
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Immunoglobulin G / metabolism
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Immunoglobulin M / biosynthesis
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Immunoglobulin M / metabolism
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Infusion Pumps, Implantable*
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Injections, Intraventricular
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Longitudinal Studies
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Mice
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Parkinson Disease / immunology
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Parkinson Disease / pathology
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Parkinson Disease / therapy*
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Putamen*
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Recombinant Proteins / administration & dosage*
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Recombinant Proteins / immunology
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Recombinant Proteins / metabolism
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
Substances
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Glial Cell Line-Derived Neurotrophic Factor
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Immunoglobulin G
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Immunoglobulin M
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Recombinant Proteins