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Vaccination against allergy

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.

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Vaccination against allergy

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  1. Vaccination against allergy Ulla Seppälä, PhD Vaccine Research

  2. 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

  3. 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.

  4. Most common sources of inhalant allergens Phleum pratense Betula verrucosa Dermatophagoides pteronyssinus Felis domesticus

  5. Vespid & Bee venom allergens Apis mellifera Vespula vulgaris

  6. Allergens and Allergen Diagnostics Allergen Diagnostics: Clinical diagnosis In vitro: specific IgE In vivo: SPT / allergen extracts

  7. What is allergy vaccination? • Allergens are administered: in different doses • at different sites } ”the immune response is changed” - Allergy vaccination Tolerance Reaction - Allergen

  8. 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 • Preventive treatment Immunotherapy is the only treatment that influence the basic course of the allergic diseases. WHO Position Paper 1998

  9. What is allergy vaccination ? Subcutaneous Immunotherpy /SCIT

  10. What is allergy vaccination ? Sublingual Immunotherapy / SLIT “Targeting the sublingual mucosa”, using single-dose droplets or tablets.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. What are the tools to cure allergy? CURRENT METHODS • natural allergen extracts • anti-allergy drugs e.g. antihistamines

  16. 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.

  17. Therapeutical recombinant proteins / rDNAs allergen + CpG/ISS/ other adjuvants 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.

  18. 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.

  19. 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.

  20. Allergen specific IgG is induced by SIT IgE = IgG4  Gabrielsson S et al, Allergy56:293, 2001.

  21. Immunotherapy: Immune deviation IgE IL-4 B-cell Allergen APC + DCs Eosinophils Th2 IL-5 Allergicresponse CD80/86 HLA CD28 CD3 + - IT - T cell - b TGF- CD4 IT Tregs IL-10 + IgG IFN-g B-cell Th1

  22. 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.

  23. ”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.

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. Conclusions A B C D “New vaccines”

  31. Optimal treatment of the allergic patient Allergen avoidance Patient education Allergy SLIT Preventive medication Specific allergy vaccination Medication Disease 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.

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