Post on 03-Jan-2016
Vaccination against allergy
Ulla Seppälä, PhD
Vaccine Research
What is Allergy ?
Non-IgE mediatedhypersensitivity
IgE- antibodies
XAllergic response(s)
• Immediate-type• Delayed- type
sensitization
What is causing the symptoms ?What is causing the symptoms ?- Sensitisation > < Clinical allergy -- Sensitisation > < Clinical allergy -
T-cell
B-cell
HLA-class II
IgM/D
T-cellAPC
BIgE
Mediator release
Mast cellIgE
CD23
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
Betula verrucosa
Felis domesticus
Phleum pratense
Dermatophagoidespteronyssinus
Vespid & Bee venom allergens
Vespula vulgarisApis mellifera
Allergens and Allergen Diagnostics
Allergen Diagnostics:
Clinical diagnosisIn vitro: specific IgEIn vivo: SPT / allergen extracts
What is allergy vaccination?What is allergy vaccination?
Tolerance
Reaction
- Allergy vaccination
- Allergen
Allergens are administered: in different doses at different sites } ”the immune response is changed”
What is allergy vaccination ?
Subcutaneous Immunotherpy /SCIT
What is allergy vaccination ?
Sublingual Immunotherapy / SLIT
Allergen Specific Immunotherapy
I.I. Anergy Anergy = clonal silence or actual clonal deletion of = clonal silence or actual clonal deletion of allergen-reactive T-cellsallergen-reactive T-cells
II.II. Immunoregulation-induced Immunoregulation-induced immune deviationimmune deviation, leading into , leading into different cytokine milieu in a target tissuedifferent 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.
Th2/Th1 Th2/Th1
SIT
IL-10/TGF-
Proposed mechanisms in immunotherapy
+ IgG4
Till SJ et al. Mechanisms of immunotherapy. J Allergy Clin Immunol 2004;113:1025-34.
Tregs/CD4+CD25+
Targeting the therapeutic tools ?
Cell mediated immunityIgG- productionDTH
IFN-
Th0
Th1
Th2
Mast cells and Basophils
IL-4PGE2
IL-12
APC
APC
IFN-
CD8+ T-cells
IL-10 -
+ IFN-
-
++
++
+ IL-4IL-4
-
-
TNF-+
T-helper-cell differentiation
APC
B-cell
Mast Cell
Allergen
Allergen
IL-4
(IL-13)
IL-5
Eosinophil
IgE
Late Phase Reaction
Sensitisation Allergic Reaction
Immediate Reaction
• natural allergen extracts• anti-allergy drugs e.g. antihistamines
What are the tools to cure allergy?
CURRENT METHODS
What are the tools to cure allergy?
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.
FUTURE METHODS
Therapeutical recombinant proteins / rDNAs
rIgs Fc-Fel d 1
allergen + CpG/ISS
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 Aluminium hydroxide Bacterial origin mucosal adjuvants Bacterial origin mucosal adjuvants – CpG ODN, CpG ODN, – Monophosphoryl lipid A (MPL)Monophosphoryl lipid A (MPL)– Cholera toxin /CT (Cholera toxin /CT (Vibrio choleraVibrio cholera)),, entero toxin /LT entero toxin /LT
((Escherichia coliEscherichia coli))Carbohydrates / (CBPs)Carbohydrates / (CBPs)Microencapsulated allergen vaccinesMicroencapsulated 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.
”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.”
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
Sauer S et al. Miniaturization in functional genomics and proteomics. Nature Reviews Genetics. 2005;6:465-76.
DNA / protein arrays+
”omics” technologies
”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
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 GelElectrophoresis after Depletion of High-Abundant Proteins. J Proteome Res. 2004;3:1120-1127.
Proteomics in Allergy ResearchProteomics 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 Identification of the disease genes or biomarkersbiomarkers
Identification of the proteins / peptides by Mass Spectrometry
DATABASE SEARCH
MW
pI
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:Biomarker discovery: PEPTIDOMICS PEPTIDOMICS
Peptides are ideal candidates for biomarkersPeptides are ideal candidates for biomarkers
Isolation/ measurement of biomarkers from blood - clinical applicationIsolation/ measurement of biomarkers from blood - clinical application
Proteases liberate biomarkers – processing and specific degradation Proteases liberate biomarkers – processing and specific degradation products – discovery tool !products – discovery tool !
HormonesHormonesCytokinesCytokinesGrowth factorsGrowth factorsetc.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.
ConclusionsConclusions
A B C D
“New vaccines”