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Vaccination against allergy Ulla Seppälä, PhD Vaccine Research What is allergy? An immunological over-reaction against specific molecules in our environment. Allergens are specific molecules / proteins against which the sensitized indivuduals are responding by producing IgE antibodies. Phleum pratense What is causing the symptoms ? - Sensitisation > < Clinical allergy CD23 Allergens IgE APC B T-cell HLA- class II IgE Mast cell T-cell “other components” B-cellIgM/D Mediator release 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 Allergy vaccination at its best ; Decrease in symptoms Decrease in use of medication Long-term effectiveness Acting on basic immunological mechanisms Anti-inflammatory treatment Causal treatment Immunotherapy is the only treatment Preventive treatment that influence the basic course of the allergic diseases. WHO Position Paper 1998 What is allergy vaccination ? Subcutaneous Immunotherpy /SCIT What is allergy vaccination ? Sublingual Immunotherapy / SLIT “Targeting the sublingual mucosa”, using single-dose droplets or tablets. Allergen Specific Immunotherapy Induction a state of tolerance by utilizing T - lymphocytes as targets I. II. 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 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. Shift from TH2 to TH1-like response following SIT for grass pollen allergy 70 60 50 40 30 20 10 0 Before SIT After 3 months After 12 months TH2 TH1 TH0 Ebner et al, Clin. Exp. Allergy, 1997, 27, 1007 -1015 Targeting the therapeutic tools ? Sensitisation Allergic Reaction T-helper-cell differentiation Late Phase Reaction CD8+ T-cells Allergen APC IL-10 - IL-12 TNF-a APC + + + + Th1 -g - + + + Eosinophil IFN-g Th0 IL-4 IL-4 IL-5 Immediate Reaction Th2 PGE2 APC Cell mediated immunity IFN-g IgG- production DTH IFN-g IL-4 Mast cells and Basophils IgE IL-4 (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. Donnelly JJ,Wahren B, Liu MA. DNA vaccines: progress and challenges. J Immunol. 2005;15;175:633-9. Therapeutical recombinant proteins / rDNAs allergen + CpG/ISS/ other adjuvants rIgs Fcg-Fel d 1 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 ”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.” 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 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. Allergen specific IgG is induced by SIT IgE = IgG4 Gabrielsson S et al, Allergy 56:293, 2001. Immunotherapy: Immune deviation IgE IL-4 B-cell Allergen APC DCs CD80/86 CD28 IL-5 HLA CD3 - IT T cell CD4 Eosinophils Th2 IT + Allergic + response - TGF-b Tregs IL-10 IFN-g Th1 + B-cell IgG 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 the disease 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 Harwanegg C & Hiller R. Protein microarrays for the diagnosis of allergic diseases: state-of-the-art and future development. Clin Chem Lab Med 2005;43:1321-6. 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 / other fluids • characterization cellular responses against natural and/or modified rDNA Ghafouri et al. Comparative proteomics of nasal fluid in seasonal allergic rhinitis. J Proteome Res. 2006;5:330-8. Proteomics in Allergy Research Fehninger T.E. et al. 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. Crameri R. The potential of proteomics and peptidomics for allergy and asthma research. Allergy 2005 Oct;60(10):1227-37. Conclusions A B C “New vaccines” D Optimal treatment of the allergic patient Allergen avoidance Patient education Allergy SLIT Specific allergy vaccination Preventive medication Disease Medication Jacobsen,L. Preventive aspects of immunotherapy: prevention for children at risk of developing asthma. Ann.Allergy Asthma Immunol. 2001; 87(1 Suppl 1):43-46.