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Allergy and Immunotherapy

Allergy and Immunotherapy. Peter Monk Infection & Immunity p.monk@shef.ac.uk. Clinical indications related to allergy. Epithelial – eczema, itching, reddening Excessive mucus production Airway constriction Abdominal bloating, vomiting, diarrhoea Anaphylaxis. Lecture Content.

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Allergy and Immunotherapy

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  1. Allergy and Immunotherapy Peter Monk Infection & Immunity p.monk@shef.ac.uk

  2. Clinical indications related to allergy • Epithelial – eczema, itching, reddening • Excessive mucus production • Airway constriction • Abdominal bloating, vomiting, diarrhoea • Anaphylaxis

  3. Lecture Content • What is allergy? • The role of immunoglobulins • The role of immune and non-immune cells • What makes an allergen? • Allergic diseases • Immunotherapies for allergy

  4. What is allergy? • Allos = other; ergon = action (Greek) • Abnormal response to harmless foreign material • Atopy = tendency to develop allergies • Rhinitis, anaphylaxis, asthma, dermatitis... • Pollen, house dust mites, animal fur, nickel, foods..... • Many ‘allergies’ are not: • Lactose, milk protein

  5. Healthcare burden of allergy • Drugs cost • $6.45 billion/pa in 2001 (USA) • Growing rapidly • Seen as diseases of developed world • Market segment increasing rapidly! • Asthma • Up to 400 million sufferers by 2025 • 1/250 deaths worldwide • Rhinitis • 500 million currently • Atopic dermatitis • 10-20% children • Food allergies • 6% young children

  6. Pathogenesis • Usually involves IgE • IgG4, IgA also • Genetic factors • Numerous! • Strong concordance in twin studies • Cells • Mast, eosinophil, lymphocytes, dendritic • Smooth muscle, fibroblasts, epithelia • Mediators • Cytokines, chemokines, lipids, small molecules

  7. Immunoglobulins: IgE • Average serum concentration: 0.3 - 100mg/ml (IgG1: 9000mg/ml) • May reach 1000mg/ml in atopic individuals • Serum half-life: 2.5d (IgG1: 23d) • Does not fix complement IgG IgE

  8. Binding of IgE to its receptor One antibody molecule binds to one receptor molecule with very high affinity

  9. IgE ReceptorsClustering causes Signalling Receptor cross linking Assembly of signalling complexes Amplification Cellular Responses

  10. IgE: Low affinity IgE receptor- FceRII, CD23 • Expression • B cells, T cells, monocytes, eosinophils, platelets, neutrophils • Function • Regulation of IgE synthesis • Triggering of cytokine release by monocytes • Antigen presentation by cells

  11. High affinity IgE receptor expressing cellsMast cell comparison with basophils/eosinophils • These are the major cell types that express a high affinity IgE receptor • Involved in host defence against parasites • Basophils (1%) and eosinophils (2.3%) circulate as mature cell types with short half-lives; • mast cells exist only in tissues • Eosinophils express a different range of granule contents to mast cells and basophils

  12. Cells: Mast cells • IgE-mediated immunity • Main effector cells • Essential? • Conserved over 500 Myrs • No humans with absence of mast cells have been reported • Heterogeneity • Primary role in innate and acquired immunity • Involved in many disease processes

  13. Mast cells: Development • Mast cells are derived from a specific cell lineage • Despite similarity to basophils, development appears to be separate • Characterised by requirement for c-kit protein • CD117 (c-kit) is a cell surface receptor for Stem Cell Factor (SCF) • Mastocytosis caused by c-kit mutations • Immature, but not mature mast cells, circulate • Mast cell precursor cell still obscure • Maturation occurs in specific tissue environments • Mast cell heterogeneity

  14. Mast Cell Morphology Semi-thin section of three rat peritoneal mast cells stained with toluidine blue. Numerous cytoplasmicmetachromatic granules are recognizable. Original magnification x1000. Left: Ultrastructure of a resting human mast cell showing a monolobed nucleus, narrow surface folds and numerous electron-dense cytoplasmic granules. Original magnification x15 000. Right: partially degranulated mast cell

  15. Mast cells – on sentry duty • Preformed Compounds • Histamine: • Arteriolar dilation, capillary leakage • Induces cholinergic reflex bronchoconstriction (bronchospasm) • Chemotactic factors • Some cytokines (e.g. IL-4, SCF) • Proteases • Tryptase • Chymase • Proteoglycans • chondroitin sulphate (?) • heparin (protease packaging?) • Mast cell chemotactic factors typically lead to eosinophil attraction and activation • Lipid derived mediators • Leukotrienes e.g. LTC4, D4, E4 • Capillary endothelial contraction with vascular leakage: Increased permeability • Prostaglandin D2 • Potent inducer of smooth muscle contraction • Platelet Activating Factor (PAF) • Increases platelet aggregation, degranulation; Increases vascular permeability; Activates neutrophil secretion • Transcription/translation • Cytokines • IL-8, IL-5, IL-4, IL-13, RANTES Mast cell derived cytokines promote a Th2 response and can lead to B cell class switching – IgE production

  16. Mast cells: Activators • Indirect activators (via IgE) • Allergens • Latex, wasp/bee venoms, foods, drugs, pollens, house dust mite faeces, animal dander • Prior sensitization is required (generally through mucosal surface) • Bacterial/viral antigens • Protein L of Pneumococcusmagnus; protein A of S. aureus • superantigens • gp120 of HIV-1 • Phagocytosis • Direct activators • Cold/mechanical deformation (asthma?) • Aspirin, tartrazine, preservatives, NO2, latex, proteases……. • Complement products (C3a, C5a) • Complement can be activated by the alternate pathway (for instance by bacterial cell surface).

  17. Mast cells and IgEResistance to parasitic infections • E.g. Schistosoma, Ascaris, Tania, Trichinella. Nippostrongylus • Multicellular organisms • Immune response characterised by Th2cytokines • IL-3, IL-4, IL-5, IL-10 • IgE response • Local mast cell activation by cross-linkage of IgE leads to the recruitment of eosinophils, macrophages and neutrophils.

  18. Mast cells and IgE: Resistance to parasitic infections • The role of IgE in combating parasitic infections would explain the presence of atopic individuals within a population. • Atopy = a hereditary predisposition to the development of immediate hypersensitivity reactions against common environmental antigens. • Are such individuals primed to respond more rapidly to parasite infections by the production of specificIgE? • In the absence of natural parasites in a clean environment, atopy is more harmful than beneficial? • It has also been suggested that the relative absence of bacterial and viral infections in western society has lead to an imbalance in the Th1/Th2 pathways for T cell response.

  19. Other cells involved in allergy • Lymphocytes • Typically Th2 • Dendritic Cells • Antigen presentation • Neurons • Coughing, sneezing etc • Other non-immune cells • Fibroblasts, epithelia, smooth muscle

  20. What makes an allergen? • Particulate delivery of antigens • HDM faeces are 20-40um • Presence of weak pathogen-associated molecular patterns (PAMP) • Weak innate immune activation • Nasal/skin delivery • Oral delivery desensitizes • Low doses • HDM faeces contain 0.2ng of allergen (Derp1, Derp2) • High doses desensitise (Cat ownership)

  21. T cell differentiation - recap T cells ‘polarise’ according to the threat detected and this determines the nature of the adaptive immune response

  22. What makes an allergen?Direct interaction with mast cells? Allergen Dendritic cell Mast cell activation produces modulators of IgE synthesis This has led to the hypothesis that allergens are responsible for IgE synthesis and allergy. DerP1 (a protease found in house dust mite faeces) and bee venom phospolipase A2 can stimulate the production of IL-4 from mast cells in the absence of IgE.

  23. Complement can direct the adaptive immune response in asthma A foreign substance that has few PAMPS but causes complement activation is opsonised and activates macrophages through C5a: adaptive immunity is not switched on. APC A foreign substance that has few PAMPS AND does not activate complement: the antigen persists and adaptive immunity is switched on. APC A complex role for complement in allergic asthma Expert Rev ClinImmunol. 2010 March; 6(2): 269–277.

  24. Allergic disease • Anaphylaxis • Allergic asthma • Allergic rhinitis (hay fever) • Contact dermatitis • Insect venom • GI: food allergies • Medication

  25. Anaphylaxis • Occurs within minutes (i.v.) or hours (GI) • Mast cell or basophil activation • IgE or direct activation • Serum tryptase, histamine elevated • CV • Vasodilation, increased vascular permeability, lowered BP • Respiratory • Bronchial SM contraction, mucus • Skin • Rash, swelling • GI • Pain, vomiting etc

  26. Allergic disease: Asthma • Complex inflammatory disease of the bronchi • 25 gene associations (interleukins, chemokines, STAT, CD14...) • Commonly triggered by allergens • House dust mites, aspergillus • Often involves eosinophil influx into lungs • Often involves IgE • Long term treatment is immune suppression

  27. Treatment strategies • Avoid allergens! • Desensitisation to allergen • Prevent IgEproduction • Prevent IgEinteraction with receptor • Prevent mast cell activation • Inhibit mast cell products

  28. Desensitisation • Immunotherapy • Increasing doses of antigen • Sub-lingual • Sub-cutaneous (SCIT) • Risks? • 23% moderate reactions; 3% life-threatening • Limited use • Atopic eczema, asthma no benefits • Usually used only for very serious conditions

  29. Preventing IgE production • Can Th2 responses be suppressed? • Mucosal delivery of allergens fused to cholera toxin subunits? • Delivery of suppressive cytokines? • IL-12 Reduces eosinophilia, Th2 responses in mice • IL-18 Reduces IgE production in mice • Blockade of cytokines? • IL-4 antagonist (Pitakinra): Reduction in late-phase response • Anti-CD23 antibodies can decrease IgE levels • Lumiliximab • Currently used for leukaemia

  30. Anti-IgE therapy • Xolair (Omalizumab) is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE). • Xolair inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) • Effective treatment for allergic asthma • Not all studies agree • Downsides • Very high cost • Slight increase in cancer incidence • Anaphylaxis • Not recommended in regions where intestinal parasites may be acquired http://csmres.co.uk/cs.public.upd/article-downloads/Polosa_2012_Drug-Discovery-Today.pdf

  31. Anti-Cytokine Antibodies • IL-5 antibody (Mepolizumab) • Phase II Improvements in some patients • CD25 and IL-2 Antibodies (Daclizumab) • Mild improvement in symptoms • Some adverse events(meningitis, cancer) • IL-25 antibody • Reduces Th2 cytokine production in mice • IL-9 antibody (MEDI528) • Prevents mast cell accumulation in mice • Phase II in humans, improves bronchospasm • TNF-alpha antibody (Infliximab) • Small trials show improvement in lung function • Risk of adverse events (infection, cancer) • Anti-cytokine vaccines?

  32. Mast cell activation • Membrane stabilisers • Cromones (sodium cromoglycate) • Beta2 agonists • Increase cAMP • Channel blockers • Signalling inhibitors • E.g. Sykkinase, Map Kinase inhibitors • Glucocorticoids • Inhibit gene transcription • Some long-term effects

  33. Mast cell products • Histamine receptor antagonists • Numerous target cells • Leukotriene, prostaglandin antagonists • Inhibit activation of Th2 cells • Tryptase inhibitors • Prevent airway smooth muscle activation • Protease-activated receptor (PAR)-2 antagonists • Numerous target cells

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