Allergy immunotherapy (mechanisms)

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Mechanisms of allergy immunotherapy

Presented by Jaichat Mekaroonkamol, MD

April24, 2014

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Allergy immunotherapy (mechanisms)

  1. 1. Allergy immunotherapy(AIT) Mechanisms Jaichat Mekaroonkamol, MD.
  2. 2. Immunotherapy for treating allergy • Allergen-specific immunotherapy • Specific immunotherapy • Allergen immunotherapy • Allergy immunotherapy (AIT) immunotherapy can include both allergen specific and non specific approaches • change the course of disease by altering the underlying natural history • aim to induce immune tolerance to allergens esp. peripheral T cell tolerance A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  3. 3. MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  4. 4. Allergic inflammation Nature Review, 2006
  5. 5. Kenny Y. Kwong et al. Advances in Pediatrics 60 (2013) 141–165
  6. 6. Immune Tolerance
  7. 7. Immune Tolerance • Immature lymphocyte • Negative selection Central tolerance • CD4+ T cell/ T helper cell Peripheral tolerance Abbas. Cellular and Molecular Immunology 7th edition
  8. 8. Abbas. Cellular and Molecular Immunology 7th edition Central: Self-tolerance • Clonal deletion • Clonal anergy T-cell: in thymus • Self MHC • Self antigen • AIRE(autoimmune regulator) B-cell: in BM • Membrane IgM/B cell Ig receptor • Functional anergy • Receptor editing (light chain) Clonal deletion
  9. 9. Abbas. Cellular and Molecular Immunology 7th edition Central: T-cell
  10. 10. Abbas. Cellular and Molecular Immunology 7th edition Central: B-cell
  11. 11. Abbas. Cellular and Molecular Immunology 7th edition Middleton allergy 8th edition Peripheral: CD4+ T cell • Anergy • Suppression • Deletion B-cell • T-dependent • Anergy -> deletion • Inhibitor reseptors • T-independent • Multivalent antigen Immunological privileged site
  12. 12. Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
  13. 13. Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell “Anergy” Lack of complete signal for T cell activation
  14. 14. Abbas. Cellular and Molecular Immunology 7th edition
  15. 15. Abbas. Cellular and Molecular Immunology 7th edition Inhibitory receptor CTLA-4
  16. 16. Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell “Suppression” Regulatory T cell • Thymus • Peripheral lymphoid organs Immature/ resting DC
  17. 17. Abbas. Cellular and Molecular Immunology 7th edition
  18. 18. The development and survival of these regulatory T cells require IL-2 and the transcription factor FoxP3 Abbas. Cellular and Molecular Immunology 7th edition
  19. 19. Regulatory T-cell Middleton allergy 8th edition
  20. 20. Treg cells directly or indirectly suppress all other effector T cell subsets Middleton allergy 8th edition
  21. 21. Middleton allergy 8th edition
  22. 22. Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
  23. 23. Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell “Deletion” T cells that recognize self antigens in the absence of costimulation may activate Bim, resulting in apoptosis by the mitochondrial pathway
  24. 24. Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell “Deletion” Repeated stimulation of T cells results in the coexpression of death receptors and their ligands, and engagement of the death receptors triggers apoptotic death
  25. 25. Peripheral: CD4+ T cell • Anergy • Suppression • Deletion B-cell • T-dependent • Anergy -> deletion • Inhibitor reseptors • T-independent • Multivalent antigen Immunological privileged site Abbas. Cellular and Molecular Immunology 7th edition Middleton allergy 8th edition
  26. 26. Abbas. Cellular and Molecular Immunology 7th edition
  27. 27. Multiple mechanisms of immune tolerance Middleton allergy 8th edition
  28. 28. MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY • Desensitization of FcRI • T cell responses • Allergen-specific IgE and IgG4 responses • Regulation of mast cells, basophils, and eosinophils A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  29. 29. Desensitization of FcεRI-bearing mast cells and basophils
  30. 30. MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY • Desensitization of FceRI • T cell responses • Allergen-specific IgE and IgG4 responses • Regulation of mast cells, basophils, and eosinophils A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  31. 31. T-cell responses • IL-10 increase is similar to the mechanisms of allergen tolerance observed in high-dose allergen exposure models • TGF-b production increases during AIT for mucosal allergies but not during AIT for venom allergy Major role in inhibiting allergic disorders A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  32. 32. Middleton allergy 8th edition
  33. 33. Middleton allergy 8th edition
  34. 34. MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY • Desensitization of FceRI • T cell responses • Allergen-specific IgE and IgG4 responses • Regulation of mast cells, basophils, and eosinophils A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  35. 35. • No evidence that it induces B-cell tolerance • Serum-specific IgE levels often transiently increase after AIT and then gradually decrease over months or years of continued treatment • Poorly correlated with clinical improvement after AIT A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  36. 36. • Increases in specific IgG4 levels accompany clinical improvement with AIT • IgG4 is considered a blocking antibody • inhibits allergen-induced and IgE-mediated release • IgE-facilitated allergen presentation to T cells • Allergen induced boost of memory IgE production A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  37. 37. Nature Review, 2006
  38. 38. MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY • Desensitization of FceRI • T cell responses • Allergen-specific IgE and IgG4 responses • Regulation of mast cells, basophils, and eosinophils A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  39. 39. Regulation of mast cells, basophils, and eosinophils • IL-10 – downregulates eosinophil function and activity – suppresses IL-5 production by human T cells • Treg cells – inhibit the FcεRI-dependent mast cell degranulation through Treg cell–mast cell contact, which leads to increased cyclic AMP concentrations and reduced Ca++ influx A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  40. 40. T reg cell • Reduced Ca++ influx • In creased cyclic AMP
  41. 41. Middleton allergy 8th edition
  42. 42. Middleton allergy 8th edition
  43. 43. CURRENT STATUS OF ALLERGEN- SPECIFIC IMMUNOTHERAPY SLIT vs SCIT • Both reducing topical steroid use and improve SCORAD in AD • SCIT: preventing venom induced anaphylaxis • SLIT has a better safety profile than SCIT • SCIT: 0.1% reported rate systemic reaction, 86% within 30 min • SLIT: local reactions fist few days and spontaneous resolve A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  44. 44. MECHANISMS OF SUBLINGUAL IMMUNOTHERAPY: SLIT • Langerhans cells, myeloid dendritic cells, and macrophages located in oral tissues, tonsils, and draining cervical lymph nodes are biased toward the induction of TH1 and IL-10 (producing CD4+ regulatory T cells) • Oral tissues contain limited numbers of mast cells located in submucosal areas, thereby explaining the well-established safety profile of SLIT, with mostly local but rare systemic reactions Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
  45. 45. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
  46. 46. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 Few proinflammatory cell 3 subsets of dendritic cells (DCs) • Langerhans cells (LCs) • oral epithelium • Myeloid APCs (MDC) • macrophage-like cells • lamina propria • Plasmacytoid DCs (pDCs) • subepithelial tissues
  47. 47. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 Few proinflammatory cell • T lymphocytes are mostly located along the lamina propria, that is, in the vicinity of numerous APCs • Include both regulatory as well as effector (TH1, TH2, or TH17) CD4+ T cells • Altogether, TH1 and Treg cells differentiated from naive T cells in oral lymphoid organs are thought to be more critical than such resident CD4+ T cells for establishing SLIT-induced tolerance
  48. 48. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 Few proinflammatory cell • MCs and Eos are found in limited numbers in oral tissues and are rather located in subepithelial areas • Oral mast cells (oMC) most likely account for adverse reactions such as oral itching and sublingual edema caused by histamine release • Differences in relative numbers of LCs and MCs have been reported, depending on the site considered
  49. 49. Allam et al. Allergy 2008: 63: 720–727
  50. 50. Allam et al. Allergy 2008: 63: 720–727
  51. 51. Allam et al. Allergy 2008: 63: 720–727 Mast cell: MC Langerhans: LC MCs appear to be closer to the mucosal surface in lingual tissues  SLIT is often associated with tongue edemas
  52. 52. Allam et al. Allergy 2008: 63: 720–727 Human oral LCs were shown to efficiently capture allergens in vitro. Such LCs express constitutively both low (CD23) and high (FceRI) affinity receptors for IgE, likely contributing to IgEmediated allergen capture. Engagement of such FcR by allergen-IgE complexes upregulates IL-10 and TGF-b secretion as well as indolamine-2- dioxygenase expression (a rate-limiting enzyme that metabolizes tryptophan), thus revealing the tolerogenic phenotype of those cells Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 The highest FcRI expression could be detected on oLC from the vestibulum
  53. 53. Allam et al. Allergy 2008: 63: 720–727 Macrophage: MC Langerhans: LC different mucosal regions such as the vestibulum might represent alternative SLIT application sites with potent allergen uptake
  54. 54. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 Few proinflammatory cell • Innate lymphoid cells • Can directly sense bacterial components and exhibit a strong capacity to produce cytokines such as IL-2, IL-5, IL-13 and IL-22 • In the absence of danger signals, the responses induced CD4+ Treg lymphocytes with a suppressive function on effector T lymphocytes • Lingual tonsils: anatomically the most important
  55. 55. PHARMACODYNAMICS OF SUBLINGUAL IMMUNIZATION • Tissues under the tongue are highly vascularized, with blood vessels draining directly into the jugular vein – small synthetic molecules (such as the vasodilator glyceryl trinitrate) with the goal to obtain a peak plasmatic release within 5 to 10 minutes – larger molecules (such as peptides or glycoproteins) are not directly adsorbed into the blood after sublingual administration Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
  56. 56. • assessing the biodistribution of iodine-123- radiolabelled Purified Der p 2 and its monomeric allergoid • 7 allergic volunteers • Assess by gel chromatography Marcello Bagnasco et al. Arch Allergy Immunol 2005;138:197–202
  57. 57. Marcello Bagnasco et al. Arch Allergy Immunol 2005;138:197–202 • Not differ between allergen and allergoid. • Plasma radioactivity began to increase only after swallowing and peaked at 1–2 h. • Both the allergen and the allergoid persisted in the mouth for several hours, and traces could be detectable up to 20 h
  58. 58. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 • allergens cross the mucosa within 15 to 30 minutes and are then captured and processed by APCs • APCs migrate within 24 to 48 hours to draining cervical lymph nodes and tonsils • CD4+ T-cell responses of the TH1 and Treg cell types are elicited within 2 to 5 days
  59. 59. Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41 • allergens cross the mucosa within 15 to 30 minutes and are then captured and processed by APCs • APCs migrate within 24 to 48 hours to draining cervical lymph nodes and tonsils • CD4+ T-cell responses of the TH1 and Treg cell types are elicited within 2 to 5 days • In patients with grass pollen allergy, the need for a 2- to 4-month pretreatment period before the pollen season • Time needed to mount a robust Treg-cell response
  60. 60. Immune change induced by SLIT Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
  61. 61. Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218 • 23 children with respiratory disease monosensitized to Dermatophagoides pteronyssinus • SLIT(n=12): glycerinated allergenic extract (SLIT® Tratamiento sublingual) • SCIT(n=11): allergen extract adsorbed in aluminium hydroxide (Pangramin® Depot-UM) • Over a 2-yr period
  62. 62. Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218
  63. 63. Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218 p < 0.05 p < 0.05 p < 0.005 p < 0.005
  64. 64. Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218
  65. 65. Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294 • 31 asthma patients allergic to HDM were studied received SLIT with a standardized Dp plus Df 50/50 extract • groups I (n = 17): 6 months • groups II (n = 14): 12 months • A group of healthy children (n = 8) • Age 8.27 ± 2.87 years, female to male ratio = 18/13
  66. 66. Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294 P= 0.03 P= 0.003 These IgAs may act as powerful anti-inflammatory antibodies, competing with IgEs for allergen binding, most particularly because they are produced at the level of mucosal surfaces. In this regard, the induction of such secretory IgAs is expected to be significantly higher after SLIT compared with SCIT Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
  67. 67. • Benefits last after discontinuation of therapy is not clear • Sustained allergens exposure likely aids in maintaining tolerance • Thus it is possible that for certain allergy indications, such as food allergy, maintaining immune tolerance is only feasible if allergen exposure is ongoing. MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
  68. 68. FUTURE OF AIT • not all patients will see improvement • carries the risk of anaphylaxis • number of administrations and the duration of the therapeutic course
  69. 69. A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.

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