The Immunology Behind Allergy Immunotherapy

1. The ImmunologyBehindAllergy Immunotherapy David Sloane, MD, EdM Allergy and Immunology Brigham and Women’s Hospital NESA 4 April, 2014

2. Disclosures • (Genentech + Novartis) Unbranded Educational Talks on Asthma • Contributor to the Mathematics Consortium Working Group

3. Objectives • 1) To review the biology of cells, antibodies, and mediator molecules responsible for allergic inflammation. • 2) To explore the rationale models for how allergy immunotherapy (IT) works. • 3) To consider the roles of omalizumabas an adjunct to subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic diseases. • 4) Participants will develop the understanding needed to educate patients about the immunology of IT.

4. Teleology • Two theories of the purpose of the immune system: • (1) Defense against microbes (Janeway) • (2) Defense against danger (Matzinger) What do you think the difference is between these two theories?

5. Immune System as a Matter Processing Network

6. Immune System as a Matter Processing Network

7. Immune System as a Matter Processing Network

8. The Whole Megilah: Allergic Reaction System Slide courtesy of Dr. Tse Wen Chang

9. Components of the System • Cells: • Dendritic Cells • T cells • B cells • Mast cells (and Basophils?) • Eosinophils • Antibodies: What are they? What are they good for? • IgE, IgG4 • Cytokines Molecules: What are they? What are they good for? • Interleukin (IL)-4, IL-13 , Thymic Stromal Lymphopoetin (TSLP) • Effector Molecules • Histamine, Leukotrienes, Prostaglandins

10. The Whole Megilah: A closer view IL4, TSLP

11. DCs provide guidance to T cells Naive T Cell Dendritic Cell Abbas, Lichtman, Pillai. Cellular and Molecular Immunology, 7th Ed

12. Costimulation or No Costimulation? Abbas, Lichtman, Pillai. Cellular and Molecular Immunology, 7th Ed

13. Th cells provide guidance to B cells Abbas, Lichtman, Pillai. Cellular and Molecular Immunology, 7th Ed

14. Antibodies: The Immune System’s Attack Dogs From Janeway et al. Immunobiology V. 2001.

15. Antibodies: The Various Species or Isotypes FromJaneway et al. Immunobiology V. 2001.

16. The Role of IgE in Allergic Inflammation • Necessary but not sufficient factor for *antigenic* stimulation of mast cells and basophils. • Prausnitz (grass) and Küstner (fish) 1920s. • Reagin identified as IgE in mid 1960s.

17. IgE: Synthesis • B cells that undergo the isotype switch to Ce produce IgE • Help from Th2 cells that express • a) CD40L and • b) IL-4, IL-13, TSLP

18. Mast Cells • Live in • mucosal layers (gut, lung) • submucosal layer • dermis • Mediators • Preformed (histamine, tryptase) [immediate] • Rapidly synthesized (PGD2, LTC4) [immediate] • Not so rapidly synthesized (cytokines) [late phase]

19. Mast Cells (and Basophils) FceRI IgE

20. Mast Cells and IgE IgE FceRI Allergen • Mediator • Release • Immediate • Late phase Mast cell granules

21. So What?

22. How do we treat Allergic Inflammation? • Avoid the allergenic trigger (“I can’t eat that”) • Antagonize the mast cell mediators (“Where’s my antihistamine?”) • Hamstring IgE (anti-IgE) • Teach the immune network not to attack (attack dogs of different breeds that compete)

23. Are Immunotherapeutic Agents Vaccines? • Traditional vaccination: • the introduction of attenuated or inactivated microbial pathogen…. (signal 1) • accompanied by adjuvant materials (signal 2) • In order to elicit the production of IgG that inhibits the microbe and elicits inflammation Abbas, Lichtman, Pillai. Cellular and Molecular Immunology, 7th Ed

24. Are Immunotherapeutic Agents Vaccines? • Allergy Immunotherapy: • the introduction of allergen …. (signal 1) • unaccompanied by adjuvant (no signal 2) • in order to elicit a T regulatory (Treg) response, leading to production of IgG4 that binds to the allergen and does not elicit mast cell activation; also production of allergen specific IgG1 and IgA. Abbas, Lichtman, Pillai. Cellular and Molecular Immunology, 7th Ed

25. Approved Indications for Immunotherapy (IT) • Allergic rhinoconjunctivitis • Allergic asthma • Insect venom anaphylaxis

26. Immunological Effects of SCIT Adkis CA and Adkis M Mechanisms of Allergen-specific Immunotherapy. 2011 JACI 127, 1: 18-27

27. Allergy Immunotherapy:If you can’t fire your old dog, get a new dog that interferes with your old dog • Introduce allergen in a non-threatening manner and context • Elicit an IL-10 and TGF-bresponse from Treg cells (natural Treg cells are the normal response in non-allergic individuals! Treg cells may also be induced) instead of an IL-4 and TSLP response from Th2cells (as seen in patients with allergies). • Thus, lead B cells to make the isotype switch to IgG4. • Also elicit IgG1 and IgA production by some B cells.

28. James LK, Durham SR. Update on mechanisms of allergen injection immunotherapy. 2008 Clinical and Experimental Allergy 38:1074-1088

29. Adkis CA and Adkis M Mechanisms of Allergen-specific Immunotherapy. 2011 JACI 127, 1: 18-27

30. James LK, Durham SR. Update on mechanisms of allergen injection immunotherapy. 2008 Clinical and Experimental Allergy 38:1074-1088

31. Effects of Allergy IT • Blunt the seasonal increase in allergen specific IgE. Therefore, less IgE on mast cells and basophils (my hairline), making them less sensitive to allergen. Evidence = inhibition of the late phase response and partial inhibition of the immediate phase.

32. Allergen Specific IgG • Maybe the IgG competes with IgEin binding allergen, thus limiting how much allergen can reach IgE on the mast cell surface and trigger mast cell activation. • Evidence = inhibition of the late phase response and partial inhibition of the immediate phase.

33. Mast Cells and IgE Allergen IgE IgG FceRI Mediator Release

34. Interference with Allergen Presentation? • Or maybe allergen specific IgG prevents the capture of allergen by IgE on the surface of professional antigen presenting cells (DCs, Macrophages, B cells). IgG

35. Mast Cell IgG Receptors • Mast cells are quite heterogeneous, depending on tissue, patient, and likely other variables. • FcgRII (CD32) and sometimes FcgRI (CD64) are expressed on some human mast cells according to some studies. • FcgRII (CD32) has an activating version (FcgRIIA) and an inhibitor version (FcgRII B). • FcgRIIB signal transduction works through a phosphatase called SHIP1. • IgG4 is proposed to bind to mast cell inhibitory receptors and blocks activation through FceRI upon allergen co-ligation.

36. Mast Cells post Immunotherapy IgE FceRI Allergen IgG4 NO Mediator Release FcgRIIb Mast cell granules

37. What about Anti-IgE? Actually, what if you could get rid of your old IgE dog?

38. The binding specificities of a therapeutic anti-IgE Slide courtesy of Dr. Tse Wen Chang

39. IgE:anti-IgE complexes 3 IgE:3 anti-IgE the largest Soluble and no immune complex problems T1/2 : anti-IgE ca. 20 days, IgE 1-2 days, IgE:anti-IgE ca. 20 days Immune complexes accumulate rapidly. Could IgE:anti-IgE complexes be beneficial? They may serve as antigen sweepers, blocking antigens to access receptors on inflammatory cells. Slide courtesy of Dr. Tse Wen Chang

40. Down regulation of FceRI in patients • FceRI density on basophils falls by 97% in 3 months. • FceRI on basophils decreases with a half life of about 3 days. • FceRI on dendritic cells are decreased substantially in two weeks. From MacGlashan DW et al., J. Immunol. 158:1438 (1997) Slide courtesy of Dr. Tse Wen Chang

41. Down regulation of FceRI in patients (cont.) From MacGlashan DW et al., J. Immunol. 158:1438 (1997)

42. What about SLIT? • Evidence of the induction of allergen specific IgG4 and IgA in some studies • Evidence of altered T cell cytokine release, including IL-10 in some studies.

43. Question 1 • Which of the following patients is an appropriate candidate for immunotherapy? • A. A 7 year old boy with peanut induced anaphylaxis • B. A 19 year old university student with pure exercise induced asthma • C. A 44 year old man with skin pustules when he is bitten by fire ants • D. A 72 year old woman with throat tightness when exposed to strong odors, episodic fatigue, and diffuse musculoskeletal complaints • E. A 13 year old girl with ocular itching, sneezing, and nasal congestion when she plays with her cat

44. Question 1 • Which of the following patients is an appropriate candidate for immunotherapy? • A. A 7 year old boy with peanut induced anaphylaxis • B. A 19 year old university student with pure exercise induced asthma • C. A 44 year old man with skin pustules when he is bitten by fire ants • D. A 72 year old woman with throat tightness when exposed to strong odors, episodic fatigue, and diffuse musculoskeletal complaints • E. A 13 year old girl with ocular itching, sneezing, and nasal congestion when she plays with her cat

45. Question 2 • Which of the following cells would you try to delete or inhibit if you wanted to block B cells from undergoing the isotypeswitch to make IgE? • A. Th1 cells • B. Th2 cells • C. Th17 cells • D. Treg cells • E. NKT cells

46. Question 2 • Which of the following cells would you try to delete or inhibit if you wanted to block B cells from undergoing the isotype switch to make IgE? • A. Th1 cells • B. Th2 cells • C. Th17 cells • D. Treg cells • E. NKT cells

47. Question 3 • Fill in the blanks to make this statement correct: A major hypothesis about how allergy immunotherapy works is the belief that ____ promotes B cells to make ____. • A. IL-4.... IgE • B. IL-13.... IgA • C. IL-10.... IgG4 • D. IL-18.... IgD • E. Fractalkine.... Thymic Stromal Lymphopoetin (TSLP)

48. Question 3 • Fill in the blanks to make this statement correct: A major hypothesis about how allergy immunotherapy works is the belief that ____ promotes B cells to make ____. • A. IL-4.... IgE • B. IL-13.... IgA • C. IL-10.... IgG4 • D. IL-18.... IgD • E. Fractalkine.... Thymic Stromal Lymphopoetin (TSLP)