Neonatal Exposure to Microbial Phosphorylcholine Modulates the Development of House Dust Mite Allergy During Adult Life

Transcription

1 Neonatal Exposure to Microbial Phosphorylcholine Modulates the Development of House Dust Mite Allergy During Adult Life J. Sides SEM Preeyam Patel Mentor: Dr John Kearney 015 CAMBAC Research Day 9/18/15 1

2 Respiratory Allergies and Asthma 1/5 Americans suffer from allergies 80% of those individuals exhibit respiratory allergies Symptoms: runny or stuffy nose, watery or itchy eyes, sneezing; can cause asthma Markers: eosinophils, mast cells, basophils, IgE

3 Asthma and Osteoporosis Up to 60%-80% children and 40% of adults with allergic rhinitis have asthma 1 Oral or inhaled corticosteroids are often used for the long-term management of asthma Patients on these treatments have higher prevalence of osteoporosis 3 Need: additional ways to both treat and prevent inflammation associated with asthma 1 Pawankar et al., APJ Allergy Imm 0 1; 00 Barnes et al., Respir Care Aug 1, Li et al., Clin Inv Med 38 ; 015

4 Hygiene Hypothesis Incidence of Infectious Diseases (%) Rheumatic Fever Hepatitis A Tuberculosis Mumps Measles Incidence of Immune Diseases (%) Chron s Disease Multiple Sclerosis Type 1 Diabetes Asthma GOAL: Elucidate the mechanisms of immune protection that early microbial exposure provides for the suppressed development of asthma Adapted from: Bach J-F, NEJM 347; Sept 00 4

5 Dust Mite Allergens Aspergillus Cockroach Apoptotic Cells Phosphorylcholine Bacteria (PC)-Bearing Organisms Streptococcus Helminths 5

6 House Dust Mite (HDM) IgE Sensitization Rate Age Cat and Dog Ragweed Mold Dust Mite Quest Diagnostics Health Trends; Allergy Report 011 Chronic and ubiquitous indoor allergen 40% of individuals with allergy are sensitized to HDM 1 89% of children with asthma have increased specific IgE to HDM Contains phosphorylcholine residues similar to those borne by Streptococcus pneumoniae 3 Lodge et al., JACI 18 4; August 011 Holt et al., JACI 15 3; December Valovirta et al., JIACI 3; 01 Nelson et al., JACI 98 ; October Patel et al., JI 194 1; June

7 Hypothesis and Methods: Hypothesis: Neonatal exposure to PC-bearing S. pneumoniae will generate PC-specific B cells capable of responding to house dust mite allergen to ameliorate the development of allergic disease Neonatal Immunization 3-4 day Methods 6-8 weeks House Dust Mite Allergy Model PBS 5ug$ 5$x$5ug$ PC-bearing pneumococcus R36A PC-deficient pneumococcus JY190 0$ 7$ 8$ 9$10$11$ 14$ 7

8 Allergic Disease T TH TH B TH TH B TH TH IgE Mediastinal Lymph Node (MedLN) 8

9 4 3 1 PBS PBS JY190 R36A 0. JY190 R36A 0.0 mm 0.00 total T cells Eos ng/ml HDM IgE ng/ml HDM-specific IgE Dust Mite-Specific HDM-Specific IgE: Serum IgE: Serum Mediastinal Lymph Node Neuts 0 PBS JY190 R36A PBS JY190 R36A Total T cells Eos Neuts macs DCs Mast Baso Cells in the BALF PBS! Airway Hyperresponsiveness JY190! 4 T15 KI! R36A! A.M.! eo! eo! neut! A.M.! A.M.! neut! eo! 0μm! neut! Rrs (cmho.s/ml) 7 ) 7) Cells Cells in the Lung (x10 in the Lung (x10 Development of Dust Mite-Induced Allergic Disease 3 R36A A.M.!JY190 PBS no HDM 1 neut! =p =p<0.01 Vaporized Methacholine (mg/ml)9 =p<0.001 Patel and Kearney, JI 194 1; June 15, 015 Published ahead of print on May 8, 015

10 50μm" 50μm" Airway Pathology PBS JY190 R36A Periodic acid-schiff stain 50μm" 50μm" Hematoxylin and Eosin 100μm" 100μm" 10

11 TH1 TH Microbial Exposure During Neonatal Life Cytokines BALF Cytokines the BALF (pg/ml)# (pg/ml) TH1-Associated Cytokines BALF Cytokines the BALF (pg/ml)# (pg/ml) 60 Allergens, Helminths TH-Associated IL- IL-1p70 IFNg IL- IL-1p70 IFN-γ IL-4 IL-4 IL-5 IL-5 IL-6 IL-6 IL-13 IL-13 IL-9 IL-9# Cytokines in the BALF (pg/ml) PBS JY190 R36A T15KI 11

12 Phosphorylcholine-Specific B Cells IgM Phosphorylcholine-BSA Pulmonary Parenchyma B Cells PBS JY190 R36A Percent of B0 + CD19 + cells in the Lung PBS JY190 R36A IgM + PC-BSA + IgM+PC-BSA+ ng/ml anti-pc IgM Anti-PC IgM BALF NS PBS JY190 R36A HDM Positive Cells (%) HDM only HDM+anti-PC IgM HDM+ISO Alv Mac DCs Macs PBS JY190 R36A Alv Macs DCs Macs Neutrophils Patel and Kearney, JI 194 1; June 15, 015 Published ahead of print on May 8, 015 Passive Anti-PC IgM ISO Anti-PC IgM 1

13 Passively Administered Anti-PC IgM is Sufficient to Decrease the Development of HDM-Induced Allergic Disease Cells in the Lung total T cells eos neuts Total T cells Neuts B cells#.0iso 1.0 total T cells Eos neuts Total T cells Eos Neut# ISO# Anti-PC IgM# Baso Baso mast Mast macsalv Eos Alvmacs Mac# MedLN Anti-PC! IgM! mm# Cells (x107)# Cells in the MLN (x107) # 14# Cells in the Lung (x105) 7)# Cells (x10 Cells in the Lung (x106) 0# 5 x 5μg# Weight Weight (mg)# (mg) 5μg# Cells (x106)# Cells in the BALF (x106) 50μg anti-pc IgM ab i.t. 1 hour prior to challenge with 5ug HDM# )# (x105) CellsCells in the(x10 BALF Cells in the BALF Cells in the MedLN ISO Anti-PC BH8 IgM # macs DCs Baso Mast ISO total B cellst cells Total T cells B cells# Patel and Kearney, JI 194 1; June 15, 015 Published ahead of print on May 8,

14 B B TH TH TH T TH TH B TH TH B TH TH IgE Mediastinal Lymph Node 14

15 Antibodies to Phosphorylcholine: Natural occurring Protective against atherosclerosis, Lupus renal disease, stroke, Alzheimer s 1 N=155 plasma samples Pediatric patients ranging from 1-15 years Diagnosed as Asthmatic or Non-Asthmatic Anti-PC IgM (ug/ml) Non-Asthmatic and perhaps asthma Asthmatic 1 15 Gronwall et al., Frontiers Imm 66 3; 01

16 Conclusions: As a preventative therapy, early childhood vaccination with PC-bearing bacteria may be a suitable therapy for HDM (and other PCbearing allergen)-induced airway disease As a treatment, anti-pc antibodies could help to dampen the development of airway disease May be a suitable therapy for asthma in place of corticosteroids 16

17 Acknowledgements: John Kearney, PhD Juan Rodriguez-Barrantes, PhD Lisa Jia Rodney King, PhD Stew New Jeffrey Sides, PhD Emily Stefanov, PhD Venkat Yeramilli, PhD Committee: David Briles, PhD David Chaplin, MD PhD Chad Steele, PhD Casey Weaver, MD Pre-Doctoral Trainee: Immunology T3 Training Grant Regulation of B Cell Clonal Diversity and Its Role in Disease R01AI J. Sides SEM 17