title: Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.
abstract: Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlapping HTT Exon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared with wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general.
authors: New York State Department of Health, Wadsworth Center, Albany, NY, USA and.
authors: Arlene I
authors: AI
authors: Ramsingh
authors: New York State Department of Health, Wadsworth Center, Albany, NY, USA and.
authors: Kevin
authors: K
authors: Manley
authors: New York State Department of Health, Wadsworth Center, Albany, NY, USA and.
authors: Yinghui
authors: Y
authors: Rong
authors: New York State Department of Health, Wadsworth Center, Albany, NY, USA and.
authors: Andrew
authors: A
authors: Reilly
authors: New York State Department of Health, Wadsworth Center, Albany, NY, USA and Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY, USA annemesser@neuralsci.org.
authors: Anne
authors: A
authors: Messer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006433:Hemocyanins; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D015854:Up-Regulation; D014611:Vaccination
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D018836:Inflammation Mediators; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin