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Vaccination against allergy. Ulla Seppälä, PhD Vaccine Research. What is Allergy ?. sensitization. IgE- antibodies. X. Allergic response(s) Immediate-type Delayed- type. Non-IgE mediated hypersensitivity. CD23. B. IgE. APC. T-cell. HLA. -. class II. IgE. Mast cell. T-cell.
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Vaccination against allergy Ulla Seppälä, PhD Vaccine Research
What is Allergy ? sensitization IgE- antibodies X • Allergic response(s) • Immediate-type • Delayed- type Non-IgE mediated hypersensitivity
CD23 B IgE APC T-cell HLA - class II IgE Mast cell T-cell B-cell IgM/D Mediator release What is causing the symptoms ?- Sensitisation > < Clinical allergy - Allergens “other components” Andersson A-C, Seppälä U, Rudin A.Activation of human neonatal monocyte-derived dendritic cells by lipopolysaccharide: Down-regulation of birch allergen-induced Th2 responses. Eur J Immunol. 2004;34(12) :3516-24.
Most common sources of inhalant allergens Phleum pratense Betula verrucosa Dermatophagoides pteronyssinus Felis domesticus
Vespid & Bee venom allergens Apis mellifera Vespula vulgaris
Allergens and Allergen Diagnostics Allergen Diagnostics: Clinical diagnosis In vitro: specific IgE In vivo: SPT / allergen extracts
What is allergy vaccination? • Allergens are administered: in different doses • at different sites } ”the immune response is changed” - Allergy vaccination Tolerance Reaction - Allergen
What is allergy vaccination ? Subcutaneous Immunotherpy /SCIT
What is allergy vaccination ? Sublingual Immunotherapy / SLIT
Allergen Specific Immunotherapy Anergy = clonal silence or actual clonal deletion of allergen-reactive T-cells Immunoregulation-induced immune deviation, leading into different cytokine milieu in a target tissue Induction a state of tolerance by utilizing T - lymphocytes as targets Rossenwasser LJ and Gelfand EW. Immunotherapy with antigens and epitopes. Am. J Repir.Cell. Mol. Biol. 1999:21;4-6.
Proposed mechanisms in immunotherapy Tregs/ CD4+CD25+ IL-10/TGF-b Th2/Th1 Th2/Th1 SIT + IgG4 Till SJ et al.Mechanisms of immunotherapy. J Allergy Clin Immunol 2004;113:1025-34.
Targeting the therapeutic tools ? Sensitisation Allergic Reaction T - helper - cell differentiation Late Phase Reaction + CD8 T - cells Allergen APC Cell mediated immunity g g IFN - IFN - IgG - production IL - 10 IL - 12 Eosinophil DTH Th1 - + g + IFN - a TNF - + + - g - Th0 - IL - 4 APC IL - 5 Immediate Reaction IL - 4 + + + Th2 PGE 2 IL - 4 APC IgE IL - 4 Mast cells and Basophils (IL - 13) Mast Cell B - cell Allergen
What are the tools to cure allergy? CURRENT METHODS • natural allergen extracts • anti-allergy drugs e.g. antihistamines
What are the tools to cure allergy? FUTURE METHODS DNA - vaccines rDNA - vaccines Reichert JM and Paquette. Therapeutic recombinant proteins: Trends in US approvals 1982 – 2002. Curr Opin Mol Ther. 2003:5;139-47.
Therapeutical recombinant proteins / rDNAs allergen + CpG/ISS Fcg-Fel d 1 rIgs Daocheng Z et al.A chimeric human-cat fusion protein blocks cat-induced allergy. Nature Medicine 2005;11(4):446-49.
Formulation of allergen vaccines by use of various adjuvants • Aluminium hydroxide • Bacterial origin mucosal adjuvants • CpG ODN, • Monophosphoryl lipid A (MPL) • Cholera toxin /CT (Vibrio cholera), entero toxin /LT (Escherichia coli) • Carbohydrates / (CBPs) • Microencapsulated allergen vaccines ”An adjuvant is an agent which, while not having any specific antigenic effect in itself, may stimulate the immune system, increasing the response to a vaccine.” Francis JN, Durham SR.Adjuvants for allergen immunotherapy: experimental results and clinical perspectives. Curr Opin Allergy Clin Immunol. 2004 Dec;4(6):543-8. Freytag LC, Clements JD.Mucosal adjuvants. Vaccine. 2005 Mar 7;23(15):1804-13.
How to monitor allergen immunotherapy ? • improved clinical phenotype • serum IgE / IgG4 –levels IgE / IgG4 • decrease in number of mast cells and eosinophils after allergen provocation • modified and/or reduced production of cytokines • BIOMARKERS ? ! Walker C and Zuany-Amorim. New trends in immunotherapy to prevent atopic diseases. TRENDS Pharm Sci. 2001;22(2):84-90.
How to monitor allergen immunotherapy ? A prequisite for a vaccine is the knowledge of how to induce Treg cells in vivo + DNA / protein arrays ”omics” technologies Sauer S et al.Miniaturization in functional genomics and proteomics. Nature Reviews Genetics. 2005;6:465-76.
”Genomics and proteomics of allergic disease” • Identification of thedisease genes; for design of new classes of anti-inflammatory compounds • Identification of expression and function of proteins; to obtain increased knowledge of mechanisms underlying allergic disease • Identifiction of novel biomarkers TODA M and ONO SJ.Genomics and proteomics of allergic disease. Immunol. 2002;106:1-10.
Microarray technology • DNA – microarrays: • High – throughput analysis and expression of multiple genes or single nucleotide polymorphisms (SNIPs). Karp CL et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 2000;1:181-7. Miklos GL, Maleszka R.Microarray reality checks in the context of a complex disease. Nat Biotechnol. 2004 May;22(5):615-21.
Microarray technology • Protein –microarrays: • examine the time course of cytokine secretion pattern by cell cultures, T- cells, DCs, Mast Cells / Basophils • examine expression profiles of cells expressing recombinant allergens Schweitzer B et al. Multiplexed protein profiling on microarrays by rolling-circle amplification. Nature Biotechnology, 2002;20:359-65.
Proteomics technology • investigation of the influence of SNIPs in gene expression and function • of the proteins = elucidation of disease gene expression • transcriptome = proteome • follow-up of the Th1/Th2/Treg – profiles • – up / down regulation of signal transduction pathways, marker molecules • plasma / serum proteomics • characterization cellular responses against natural and/or modified rDNA Chromy BA et al. Proteomic Analysis of Human Serum by Two-Dimentional Differential Gel Electrophoresis after Depletion of High-Abundant Proteins. J Proteome Res. 2004;3:1120-1127.
Proteomics in Allergy Research Fehninger T.E. etal. Exploring the context of lung proteome within the airway mucosa following allergen challenge. J Proteome Res. 2004;3:307-20.
Identification of the disease genes or biomarkers pI MW Identification of the proteins / peptides by Mass Spectrometry DATABASE SEARCH Weingarten P et al. Application of proteomics and protein analysis for biomarker and target finding for immunotherapy. Methods Mol Med. 2005;109:155-74.
Biomarker discovery: PEPTIDOMICS • Peptides are ideal candidates for biomarkers • Isolation/ measurement of biomarkers from blood - clinical application • Proteases liberate biomarkers – processing and specific degradation products – discovery tool ! • Hormones • Cytokines • Growth factors • etc. • Schulte I. et al. Peptides in body fluids and tissues as markers of disease. • Expert Rev Mol Diagn. 2005 Mar;5(2):145-57.
Conclusions A B C D “New vaccines”