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1.
PLoS One ; 8(8): e72301, 2013.
Article in English | MEDLINE | ID: mdl-23977276

ABSTRACT

Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer's disease. The unmet need of effective therapy for Alzheimer's disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuro-inflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimer's disease.


Subject(s)
Alzheimer Vaccines/immunology , Antibodies, Neutralizing/blood , Peptides/immunology , Phosphoproteins/immunology , Tauopathies/drug therapy , tau Proteins/immunology , Alzheimer Vaccines/administration & dosage , Animals , Brain/drug effects , Brain/immunology , Brain/physiopathology , Disease Models, Animal , Humans , Liposomes/chemistry , Mice , Mice, Transgenic , Peptides/administration & dosage , Peptides/chemical synthesis , Phosphoproteins/administration & dosage , Phosphoproteins/chemical synthesis , Phosphorylation , Psychomotor Performance/drug effects , Tauopathies/immunology , Tauopathies/physiopathology , Treatment Outcome , Vaccination , tau Proteins/antagonists & inhibitors , tau Proteins/genetics
2.
Blood ; 121(1): 85-94, 2013 Jan 03.
Article in English | MEDLINE | ID: mdl-23144170

ABSTRACT

Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell-independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-ß (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.


Subject(s)
Adaptor Proteins, Vesicular Transport/physiology , Amyloid beta-Peptides/immunology , B-Lymphocytes/immunology , Immunoglobulin Class Switching/immunology , Peptide Fragments/immunology , Toll-Like Receptor 4/physiology , Vaccines, Subunit/immunology , Adaptor Proteins, Vesicular Transport/deficiency , Adaptor Proteins, Vesicular Transport/genetics , Adoptive Transfer , Amino Acid Sequence , Amyloid beta-Peptides/administration & dosage , Animals , Antigen Presentation , B-Lymphocytes/metabolism , CD28 Antigens/deficiency , CD28 Antigens/immunology , CD40 Ligand/deficiency , CD40 Ligand/immunology , Germinal Center/immunology , Histocompatibility Antigens Class II/immunology , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Lipopolysaccharide Receptors/immunology , Liposomes , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Molecular Sequence Data , Ovalbumin/administration & dosage , Ovalbumin/immunology , Peptide Fragments/administration & dosage , Receptors, Antigen, B-Cell/immunology , T-Lymphocytes/immunology , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/genetics , Vaccination , Vaccines, Subunit/administration & dosage
3.
J Biol Chem ; 286(16): 13966-76, 2011 Apr 22.
Article in English | MEDLINE | ID: mdl-21343310

ABSTRACT

Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be modulated post-liposome assembly by the addition of distinct small molecule ß-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing ß-sheet aggregated lipopeptide (Palm1-15) induced polyclonal IgG antibodies that specifically recognized ß-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases, such as Alzheimer disease.


Subject(s)
Liposomes/chemistry , Peptides/chemistry , Proteostasis Deficiencies/metabolism , Vaccines/chemistry , Alzheimer Disease/metabolism , Animals , Benzothiazoles , Circular Dichroism , Female , Humans , Immunoglobulin G/chemistry , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred C57BL , Protein Conformation , Protein Folding , Protein Structure, Secondary , Protein Structure, Tertiary , Thiazoles/chemistry
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