The Biology Of And. Thomas B. Casale, MD. Professor of Medicine Chief, Allergy/Immunology Creighton University Omaha, NE

Transcription

1 The Biology Of IgE And Anti-IgE Thomas B. Casale, MD Professor of Medicine Chief, Allergy/Immunology Creighton University Omaha, NE

2 Objectives To review IgE synthesis, including local production To review IgE structure To discuss IgE levels and associated conditions To understand FceRI and CD23 expression and consequences of engagement by IgE To discuss the clinical and biologic effects of IgE and anti-ige

3 IgE Production and Subsequent Involvement in Allergic Disease Sensitization Allergen Allergen Re-exposure Environment Submucosa Antigen presenting cell MHC class II protein and epitope Production of antigenspecific IgE Mast cell degranulation Clinical effects Th2-cell + B-cell Mediators asthma, hayfever, urticaria

4 Molecular Genetic Control of IgE Synthesis Initially, all B cells produce IgM B cells switch isotype and retain their original antigenic specificity IgE antibody production is triggered by soluble factors and cell surface interactions Genomic DNA is spliced and rejoined (deletional switch recombination or class switch recombination, CSR) Recombination requires deletion Oettgen HC, et al. J Allergy Clin Immunol 107: , 2001 Adapted from Immunobiology of IgE ; Medical media Communications; 2005 Chaudhuri, J et al. Advances in Immunology 94: ,2007 Durandy, A et al. Advances in Immnology 94: , 2007

5 Summary of IgE Synthesis Events T h 2 Signal 1* emrna Germ-line Transcription B Cell Signal 2 B-cell Activation & Class Switch Recombination T Cell Basophil IL-4 IL-13 CD40 CD154 Mast Cell IgM CD40 Engagement via Physical Association (and other co-stimulatory molecules) B Cell IgE

6 T/B Cell Interactions Leading to IgE Isotype Switching 1. Ag binding and processing 2. Ag presentation & engagement of TCR/CD3 complex by MHC class II molecules 3. Rapid expression of CD Engagement of CD40 5. Increased CD80-CD86 expression 6. T/B cell interactions via CD40/CD154 amplified by interactions between co-stimulatory molecules, particularly CD28/CD80-CD86 7. High-rate transcription and secretion (8) of IL-4 and/or IL IL-4/IL-13 receptor binding 9. IL-4 triggers ε germline transcription 10.DNA recombination to the targeted ε S region 11.IgE isotype switching 12.IgE secretion Middleton s Allergy, Fig. 7.1

7 IgE Class Switch Recombination Variable Region Genes Constant Region Genes

8 Summary Of Important IgE Synthesis Events Synthesis of IgE is tightly controlled & requires CSR plus: Specific cytokines: Positive: IL-4 and IL-13 and IL17a Negative: IFN-g via STAT1 and SOCS1 Specific surface molecular interactions: TCR/MHCII; CD40/CD154; CD28/CD80/86 Specific transcription factors Positive: STAT6; NFkB; BSAP Negative: BCL6; ID2; SOCS1

9 Genetic Regulation Of Total IgE Levels Regulation of serum IgE production is largely influenced by familial determinants. Evidence of a strong genetic contribution to the variability of total IgE levels that is independent of specific IgE responses: total serum IgE levels are under stronger genetic control than atopic disease GWAS indicate several putatively important loci FCeR1a RAD50/IL-13 cluster STAT 6 Weidinger S et al. Curr Opin Allergy Clin Immunol Oct;10(5):408.

10 IgE Structure S Dreskin Board Review

11 Least abundant Ig: IgE Levels ~150 ng/ml vs. 10 mg/ml for IgG (~66,000 fold less) Increase from birth through age 10 Preschool levels do not correlate well with those at older ages Largely produced by plasma cells in the mucosalassociated lymphoid tissue T1/2 of plasma IgE = 1 to 5 days T1/2 of mast cell-bound IgE ~ 2 weeks Gould, HJ et al. Annual Rev. Immunol. 21: , 2003 Prussin C, et al. J Allergy Clin Immunol 111:S486-94, 2003 Nickel et al. Clin Exp Allergy 2005; 35:

12 Lessons From IgE Deficiency Mice with IgE deficiency are capable of: Anaphylaxis (H Oettgen et al, Nature, 1994) Clearing parasites ( N Watanabe et al, PNAS, 1988) Patients treated with omalizumab: Develop anaphylaxis Slight increased risk of geohelminth infection, OR=2.2 (0.94,5.15) in 1 year Brazilian trial (Cruz et al, Exp Clin Allergy, 2007) IgE deficiency in humans is rare, but associated with: Recurrent sino-pulmonary infections (familial IgE deficiency) Autoimmune diseases

13 Non-Allergic Conditions With Elevated IgE Infections with organisms having superantigens Parasitic infections (? protective role) Non-parasitic infections (HIV, TB, candidiasis, CMV) Tobacco smokers Cutaneous diseases (e.g. Bullous pemphigoid) GVHD Neoplasms (e.g. Hodgkin's) Inflammatory diseases (eg, Kimura disease, Churg-Strauss, and Kawasaki disease) Cystic fibrosis

14 Immunodeficiencies With Elevated IgE Hyper-IgE syndrome (predominantly polyclonal) Netherton s disease (cutaneous ichthyosis) Wiskott Aldrich syndrome (eczema & thrombocytopenia) IPEX: Immune dysregulation, Polyendocrine enteropathy, X-linked syndrome Omenn syndrome Atypical complete DiGeorge syndrome

15 IgE and Allergic/Respiratory Diseases Increased serum IgE associated with: Atopic Dermatitis ABPA Asthma prevalence (w/ and w/o atopy) Persistent wheezing in children Airway hyper-responsiveness 1 Epidemiologic and empirical evidence confirms a clear relationship between IgE and both pathogenesis and symptoms of respiratory disease 2,3 1 Schmidt D, et al. Clin Exp Allergy 2000;30: Burrows B, et al. N Engl J Med 1989;320: Oettgen HC, Geha, RS. J Allergy Clin Immunol 2000;107:

16 Prevalence of Asthma Related to Serum IgE Level Standardized for Age and Gender Prevalence of Asthma (%) 40 Age 6 to <35 years Age 35 to <55 years 30 Age 55+ years < to < to < to < Ranges of serum IgE Z score Burrows B, et al. N Engl J Med 1989; 320:

17 Longitudinal Association Between IgE & Lung Function in Adult Asthmatic Non-Smokers FEV1/FVC (%) 85 Log IgE = 0.8 Log IgE = Age (yrs) Sherrill DL, et al. Am J Respir Crit Care Med 1995;152:

18 Local IgE Production Occurs In Multiple Target Organs Nasal mucosa: allergic & nonallergic rhinitis & CFS Nasal Polyps (also can involve Staph) Bronchial mucosa: Predominately in asthma Regardless of atopic status Possibly due to superantigens (Staph enterotoxins) Related to asthma severity Adenoids Clinical implications: Strategies aimed at blocking IgE locally could be fruitful 1 Cameron et al, J Immunol, Coker et al, J Immunol, 03 3 Takhar et al, J Immunol, 05 4 Takhar et al, JACI, 07 5 Shin et al, Ped Allergy Immunol, Suh et al, Clin Exp Allergy, 04

19 Atopy & Entopy Powe DG, et al, Allergy Jul;40(7):987.

20 % Subjects Entopic Rhinitis NAPT-DP Nasal allergen provocation test with DP sige-dp PNAR PAR Rondo n, et al, JACI, 07

21 High-and Low-Affinity IgE Receptors High Affinity FceRI a FceRI FceRII (CD23) Low Affinity FceRII 10-7 g g

22 CD23 Is Transcribed In 2 Splice-isoforms CD23a: Largely restricted to B cells CD23b: T cells, dendritic cells, monocytes, neutrophils macrophages, eosinophils & intestinal epithelial cells Membrane bound functions include: Regulation of IgE synthesis: binding of IgE to B cell CD23 inhibits IgE synthesis Ag capture for presentation Growth and differentiation of B cells IgE and IL-4 up-regulates CD23 expression IFN-α inhibits IL-4-induced CD23 expression

23 Pleotropic Effects of scd23 CD23 can be shed from membrane into scd23 by endogenous proteases (ADAM10, Der p 1) NO and camp production and cytokine release from monocytes via integrin receptors scd23-ige complexes can interact with CD21: Stimulating IgE synthesis when CD23 is trimeric Repressing IgE when CD23 is monomeric Acharya M, et al. Clin Exp Immunol Oct;162(1):12 Burton OT, Oettgen HC. Immunol Rev. 2011;242(1):128.

24 Mean % Change in IgE Concentration Effect of Single Dose of Anti-CD23 on IgE Concentration IDEC-152 Dose Group (mg/kg) 0.05 (N = 3) 0.25 (N = 3) 1.0 (N = 4) 4.0 (N = 4) 10.0 (N = 5) 15.0 (N = 5) Placebo (N = 6) / Study Day Rosenwasser et al. JACI,116:563; 2003

25 Binding of IgE to FceRI Allergen binding site F (ab ) 2 Ce1 V H C L V L IgE IgE binds to a chain and g chains are involved in signal transduction FceRI Ce2 Ce3 a 2 a 1 Ce4 Fc Out Cell membrane In Holgate S. QJM 1998;91: a g g

26 Engagement Of High Affinity IgE Receptor Burton OT, Oettgen HC. Immunol Rev. 2011;242(1):128.

27 Beneficial Effects Of IgE Defense against pathogens (parasitic) Allergen avoidance / early warning system Antigen capture for presentation Job Security

28 Biologic Effects Of IgE Crosslinking Of FceRI leads to mast cell/basophil degranulation IgE increases mast cell survival Monomeric IgE can lead to mediator release Log-linear Relationship Of IgE levels to FceRI expression

29 IgE-Dependent Release of Inflammatory Mediators Leading To Early/Acute Asthma Symptoms IgE FceRI Allergens MAST CELL Immediate Release Preformed Mediators: Histamine, TNF-a, Proteases, Hydrolases, Proteoglycans(Heparin) Over Minutes Lipid mediators: Prostaglandins Leukotrienes Thromboxanes Over Hours Cytokine production: ILs-3,4, 5,6,8,9,11,13 TNF-a, MIP1, MCP Mucus Production Mucosal Edema Bronchoconstriction Chemotaxis Asthma Symptoms Chronic Inflammation

30 IgE- Mediated Allergic Reactions Bacteria Epithelium Allergens Secretion and Epithelial Permeability Immune-cell Recruitment and activation Blood flow coagulation and vascular permeability Neutrophil Histamine, LTC 4, Chymase, and heparin Blood vessel endothelium Adapted from Bischoff, Nature Immunol, 07 TNF Histamine, LTC 4 and PGD 2 IgE Mast Cell ILs-3,4, 5,6,8,9,11,13 TNF-a, MIP1, MCP Eosinophil B-cell T-reg Cell Immune cell activation and recruitment many of these cells have IgE receptors TGFβ and FGF Histamine, PGD2, and proteases Nerve cell Wound healing and fibrosis Fibroblasts Smooth Muscle Cell Neuroimmune interactions, Peristalsis bronchoconstriction and pain

31 IgE Promotes Survival Of Cultured Human Lung Mast Cells Through IL-6 Cruse et al, BMC Immunology, 08

32 Activation Of Human Lung Mast Cells By Monomeric IgE Cruse, et al, ERJ, 05

33 Effects Of IgE On Its Receptors: Prevention Of Internalization and Degradation No effect on transcription Burton OT, Oettgen HC. Immunol Rev. 2011;242(1):128.

34 FceRI (% of baseline) Omalizumab Rapidly Decreases Basophil FceRI Expression 120 Omalizumb Placebo * 20 * * * 0 Day 0 Day 7 Day 14 Day 28 Day 42 *P < Lin H, et al. J Allergy Clin Immunol. 2004;113:

35 Potential Clinical Uses of Omalizumab Asthma (atopic and non-atopic) SAR and PAR- w/ or w/o asthma Atopic Dermatitis Food Allergy Insect Allergy Chronic Urticaria w/ and w/o autoantbodies ABPA Latex allergy Chronic hyperplastic sinusitis Recurrent nasal polyposis Drug Allergy Idiopathic anaphylaxis Casale & Stokes. JACI, 2009

36

37 Omalizumab Indications Moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with ICS. Step 5/6 care (NHLBI) or 4/5 (GINA)

38 Effects Of Omalizumab On Airway Inflammation In Mild Atopic Asthmatics 5-center, double blind, placebo-controlled, parallelgroup, 16-week study (n=44) : Reduction in submucosal eos: 8.0 to fold reduction in IgE+cells - Decreases in FCeRI cells Decreases in B cells, and CD3+, CD4+, and CD8+ cells implies that IgE plays an important role in airway inflammation in asthma R Djukanovic, et al, AJRCCM,170:583,2004

39 Omalizumab Decreases FceRI+ Cells in Bronchial Biopsies Pre-Omalizumab Post-Omalizumab Djukanović R, et al. Am J Respir Crit Care Med 2004;

40 Clinical Effects Of Omalizumab: Pooled data from 7 trials In patients on ICS alone, or in combination with other agents, addition of omalizumab: Reduced number of exacerbations (40-50%) Reduced symptom scores Reduced need for inhaled corticosteroids Reduced use of rescue medication Improved asthma-related quality of life Consider using in patients with poor control despite optimal care 1 Busse W et al. J Allergy CLin Immunol 2001;108: Soler M et al. Eur Respir J 2001;18: Humbert M, et al. Allergy 2005;60:

41 Omalizumab In Children 6-11 Avg FP dose 515 mcg 2/3 on LABA 1/3 on LTRA Lanier et al. JACI.2009;124:1210-6

42 Omalizumab and Seasonal Asthma Exacerbations In 6 to 20 y/o NEJM, 3/11

43 Omalizumab and Asthma Summary Omalizumab is effective in children and adults in reducing exacerbations and steroid requirements Also positive effects on SABA use, QOL, Sxs and PFTs (minor) Omalizumab has anti-inflammatory effects If not effective by 4-6 months, probably will not be effective Predictors of who will respond are unclear Whether omalizumab can be stopped with sustained clinical efficacy is unclear May depend on duration of treatment

44 Non-Asthma Potential Uses Of Omalizumab

45 Potential Clinical Uses of Omalizumab SAR and PAR- w/ or w/o asthma Casale, et al, JAMA, 01

46 Seasonal Allergic Rhinitis: Could Omalizumab Be Cost Effective? Omalizumab- induced maximal inhibitory responses: - IgE: 1 day - FceRI: 14 days - Nasal Challenges: 14 days It could be a useful agent to quickly control allergic respiratory symptoms. Data Suggest that pre-/co-seasonal administration could be cost effective Lin et al, JACI;2004

47 Potential Clinical Uses of Omalizumab, Cont d SAR and PAR Atopic Dermatitis Food Allergy

48 Effects Of Omalizumab On Peanut Challenges Mg Of FlourTolerated 5 PL and 9 Omal peanut Baseline Week Placebo Omalizumab Sampson et al, JACI, 2011

49 Potential Clinical Uses of Omalizumab, SAR and PAR Atopic Dermatitis Food Allergy Insect Allergy Cont d Two reports of VIT successfully administered after ~ 2 weeks of omalizumab (one patient w/ mastocytosis)

50 Potential Clinical Uses of Omalizumab, Cont d SAR and PAR Atopic Dermatitis Food Allergy Insect Allergy Chronic Urticaria/Angioedema With and w/o Autoantibodies (incl TPO) Physical Urticarias Mastocytosis

51 Treatment Of Chronic Urticaria With Omalizumab 90 Patients Chronic Antihistamine-Resistant Urticaria Treated with Omalizumab Remission w/i 72 hrs Sustained with 150 mg/mo Saini et al. JACI, 2011 Romanao et al, Ann Allergy, 2010

52 Effects of Omalizumab on Cold-Induced Urticaria/Anaphylaxis Diagnostic Test: Therapy: Special Features: Ice Cube for 5-15 min Antihistamines, Tolerance Transferable Factor Before Treatment After 6 Months J Boyce, JACI, 06

53 Potential Clinical Uses of Omalizumab, Cont d SAR and PAR Atopic Dermatitis Food Allergy Insect Allergy Chronic Urticaria with Autoantbodies Adjuvant to Immunotherapy: Increased Efficacy As Add On Improved Safety As Pretreatment SCIT and oral IT for milk

54 Study Design Casale, et al,jaci, 06

55 Average Allergy Severity Scores Over the Primary Ragweed Season for the PP Sample P=0.020

56 % of Patients Anaphylaxis Within 0-7 Hours of RIT* % reduction P=0.026 Omal+IT Omal+Pl PL+IT PL+Pl Omal+IT Omal+Pl Pl+IT Pl+Pl *Post-Hoc Analysis

57 What About Pretreatment In Patients With Asthma? A 26-week, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the effect of Xolair (omalizumab) on improving the tolerability of specific immunotherapy in patients with at least moderate persistent allergic asthma* inadequately controlled with inhaled corticosteroids FEV1 > 75% * + ST to HDM, cat or dog Massanari et al, JACI 2010

58 Omalizumab and Immunotherapy: Study Design 150 Patients per arm, Randomized 1:1 Omalizumab Cluster IT Maintenance IT Screening Placebo Cluster IT Maintenance IT 3 wk overlap Period 1 Period 2 Period 3 Period 4 Visit 0 Visit 1 Visit 5 Visit 11 Visit 14 Visit 19-2wks 0 13wks 16 wks 17 wks 24 wks

59 Percent SARs Proportion of Patients Who Experienced A Systemic Allergic Reaction: Primary Endpoint 30.0% 25.0% 26.2% P= % 15.0% 13.5% 10.0% 5.0% N = 32 N = % N=122 N=126 Placebo Omalizumab

60 Rapid Oral Desensitization In Combination With Omalizumab In Patients With Cow s Milk Allergy 11 children (7-17 y/o) with cow s milk allergy Elevated milk-specific IgE ( kua/l) 9 wks after start of omalizumab, oral cow s milk desensitization performed in 2 phases: 0.1 mg of milk powder with doses Q 30min to max of 1000 mg (cumul dose, 1992 mg) Weekly incr in doses over next 7 to 11 wks Omalizumab D/C at week 16 DBPCFC done 8 wks later All 9 patients who reached daily dose of 2000 mg passed the DBPCFC & tolerated >8000 mg/d Nadeau et al, JACI, 2011

61 Omalizumab and IT Conclusions Pretreatment with omalizumab: Added efficacy and safety to SCIT Allowed more patients to reach maintenance Added efficacy and safety to OIT Unanswered questions: How long do you need to treat with both? Can you stop the omalizumab after reaching maintenance IT?

62 Potential Clinical Uses of Omalizumab SAR and PAR- w/ or w/o asthma Atopic Dermatitis Food Allergy Insect Allergy Chronic Urticaria with Autoantbodies Adjuvant to Traditional Immunotherapy Other IgE-Dependent Diseases

63 Additional Potential Uses Of Omalizumab ABPA AERD with NSAID intolerance Latex allergy Chronic hyperplastic sinusitis Recurrent nasal polyposis Non-allergic asthma Drug Allergy Idiopathic anaphylaxis Others

64 Effects Of Omalizumab On ABPA in Cystic Fibrosis K van der Ent, Thorax. Vol 62, 2007

65 Effects Of Omalizumab On Latex-Induced Allergy: Conjunctival Challenge Leynadier, et al,jaci, 2004

66 Effects Of Omalizumab ( 4 mos.) on Chronic Rhinosinusitis: 68 y/o with 20 yr h/o ASA-triad pre post Grundmann et al, JACI, 2008

67 Effects of Omalizumab on Clinical Parameters Of Idiopathic Anaphylaxis Warrier and Casale, Ann Allergy Asthma Immunol FEV1 Oral steroid courses/year Before Omalizumab* After Omalizumab Before Omalizumab** After Omalizumab Anaphylactic episodes/year School days missed/year Before Omalizumab** After Omalizumab Before Omalizumab** After Omalizumab *2 weeks before Omalizumab was started; **Average of preceding 5 years

68 Conclusions Elevated IgE associated with: Many allergic / respiratory diseases Asthma and AWH Atopic dermatitis Non-allergic conditions IgE plays a key role in pathogenesis of allergic diseases Mast cell/basophil degranulation Regulation of FceR1 and CD23 expression Mast cell survival Ag presentation

69 Conclusions Since IgE plays an important role in a number of diseases, strategies aimed at blocking the effects of it will likely prove important.. Not just for asthma Omalizumab has many potential therapeutic applications Small, easy to make and deliver antagonists should be pursued, especially those that. Induce tolerance