induced respiratory allergic diseases

NOVEL APPROACHES IN THE PREVENTION,

DIAGNOSIS, AND THERAPY OF RAGWEED-

INDUCED RESPIRATORY ALLERGIC DISEASES

Prof. Carmen Panaitescu Bunu, MD PhD

Timisoara, 26 April 2016

University of Medicine and Pharmacy Victor

Babes Timisoara

Topics

• Immunological mechanisms of allergy - rationale for treatment and

prevention of allergic diseases

• New trends in allergic asthma treatment

• New trends in allergen-specific immunotherapy (SIT)

• Timisoara experience and INSPIRED project

Allergy - disease of the 21st century

• Hay fever

– Allergic rhinitis (10-30%)

– Allergic conjunctivitis

Allergy – multifaceted disease

• Skin allergy

– Atopic dermatitis

– Urticaria (20%)

• Food allergy

(250 000 000 people)

• Bronchial asthma (235 000 000

patients, 250 000 deaths/year)

• Anaphylaxis

WHO-World Allergy White Book 2011-2012

WAO estimates that allergy prevalence in the whole

population by country ranges between 10 - 40%

3

Valenta R, Nature Reviews Immunology, 2002

Development of the allergic immune response

4

IgE – “key player” in allergic inflammation

Galli SJ, Nat Med, 20135

Topics






Potential points of therapeutic intervention along the

allergy pathway

Hawrylowicz, Nat Rev Immun 2005

Block initiation of

immune response Block Th2

activation

Block effector

molecules of

allergy

7

Casale, JACI 2008

CCR

Anti-IL5

IL-4

IL-13

IL-9

Anti-IL9

Anti-IL4Anti-

IL4Rαααα

Anti-IL13

Anti-IgE

Omalizumab

New trends in allergic asthma treatment: immunomodulation

2005

2015

1. Milgrom B, et al. N Eng J Med 1999;1341(26), 1966–73

SCIT

1903

Topics






SIT mechanisms

Cezmi A Akdis, Nature Medicine, 201210

Immunomodulation induced during SIT

Norman, J Allergy Clin Immunol 2004

1. Mc+Ba

2. Treg

3. IgE

4. IgG4

5. Prick test

6. Tissue Eo

11

A century of SIT - Critical points

Valenta, JIM 2012

1903

Oral administration of

pollen extract for SIT

(Black)

1927

Adsorption of

allergens onto

aluminium salts for SIT

(Sledge)

1938

Subcutaneous injection of

grass-pollen extract in

allergic patients reduces

allergic symptoms (Noon)

1911

SIT induces an allergen-

specific serum factor that

inhibits allergic reactions

(Cooke)

1935

Controlled SIT

study (Frankland)

1954

Coupling PEG renders

allergens nonallergenic and

tolerogenic (Lee & Sehon)

1977

SLIT for tolerance

induction

(Scadding&Brostoff)

1986

Synthetic allergen-derived

T-cell epitope-containing

peptides for SIT (Norman)

1996 2002

First SIT with recombinant

hypoallergenic allergen

derivatives (Niederberger)

2004

SIT with purified allergen

conjugated to immunostimulatory

DNA sequences (Creticos)

2006

SIT prevents progression

towards severe allergy

(rhinitis–asthma) (Moller)

Pollen-specific anti-sera

neutralize pollen-induced

allergic reactions (Dunbar)

Ideal immunotherapy

13

New approaches to SIT

14

From allergen genes to allergy vaccines

Valenta & Niederberger, Annu Rev Immun 201015

cDNA sequence

mRNA

Allergen sources

reverse transcription

Recombinant allergen sequence

Three-dimensional allergen structure

Production of recombinant allergens

Nandy, Allergo J Int 2015

Biotechnology used by Biomay GmBH Austria for production of

grass pollen and house dust mite recombinant allergens for SIT

⇓

New step: ragweed SIT

16

Dillemas regarding SIT with recombinant allergens

17

SIT side effects

Focke, Clin Exp Allergy 201018

Strategies for decreasing SIT adverse effects

Valenta & Niederberger, Annu Rev Immun 201019

Topics






Aim of study

1. Determine the relevant indoor and outdoor allergens in the Western region of

Romania

2. Determine the impact of sensitization to ragweed pollen in patients from the

Western region of Romania

3. Evaluate and compare the immune response of patients allergic to different

ragweed species, in order to assess:

• Patient exposure to different ragweed species (A. artemisiifolia and A.

trifida)

• Sensitivity and specificity of allergen microarray ImmunoCAP ISAC for

specific serum IgE

• Cross- or co-sensitization between ragweed species

21

Material and methods

22

Ragweed pollen in the Western part of Romania

2000 - 2009

Concentration

Linear (concentration)

23

Results

Polysensitized and monosensitized patients 2008 - 2014

24

Results

25

Results

Monosensitized patients 2008 - 2014

26

Recombinant Amb a 1 for production of a

hypoallergenic vaccine

• Study: Cross-sectional observational study performed with Biomay GmBH

Austria/MUW and DIATER Laboratorios, Spain

• Duration: July – November 2014

• Subjects with allergic rhinoconjunctivitis ± allergic bronchial asthma (according

to ARIA and GINA criteria):

– Group I: 97 patients (89 allergic + 8 non-allergic controls)

– Group II: 25 patients (allergic to ragweed)

• What:

1. SPT with commercially available aeroallergen extracts (“gold standard”)

2. Microarray for component-resolved diagnosis: specific serum IgE using

ImmunoCAP ISAC → MedALL microchip, which includes 176 different proteins

(FP7) (97 samples)

3. Immunoblotting and ELISA inhibition to A. artemisiifolia and A. trifida pollen

extracts to assess cross- or co-sensitization between the two spp (25 samples)

27

Ragweed study

• 97 subjects included:

84 patients allergic to ragweed pollen

13 controls5 allergic to other aeroallergens

8 nonallergic

Mild intermittent allergic

rhinitis

Mod-severe intermittent

allergic rhinitis

Mild persistent allergic

rhinitis

Mod-severe persistent

allergic rhinitis

28

Microarray for component-resolved diagnosis

ImmunoCAP ISAC

microarray chip

Valenta, Viena 2013

MedALL microchip

including 176 different

proteins

29

Patient distribution

Monosensitized to Ambrosia

Polysensitized

Polysensitized

to pollens

Polysensitized

to various

aeroallergens

30

ImmunoCAP ISAC Amb a 1

Method:

Standard microarray, at the Pathophysiology and Allergy Department

Medical University Vienna,

Prof. Rudolf Valenta

Microarray chip with 176 allergens / sample

n = 84

Class 0

Class 1

Class 3

Class 4

31

ImmunoCAP ISAC vs Prick test (ragweed) correlation

32

Results – Immunoblotting Amb a vs Amb t

Courtesy of Mr. Fernando Pineda de la Losa

Amb a 1

Amb a 11?

Amb a 6-10

33

Results – ELISA inhibition

Courtesy of Mr. Fernando Pineda de la Losa

ELISA inhibition Amb a vs. Amb t

(serum pool from clinically characterized ragweed allergic subjects)

34

Conclusions

• In the Western part of Romania, the most important clinical relevant

allergens are

– Outdoor - ragweed pollen

– Indoor - house dust mites

• The vast majority of patients allergic to ragweed pollen are sensitized

specifically to A. artemisiifolia

• There is no significant cross- or co-sensitization between A. artemisiifolia and

A. trifida

• Ragweed may contain other clinically relevant allergens besides Amb a1 that

should be identified and introduced in the component-resolved diagnosis kit,

as well as in a future immunotherapeutic product

– A better characterization of T and B cell epitopes from ragweed pollen is

required for a better therapeutic approach

35

Conclusions

• SIT represents the only disease-modifying therapy in allergy

– Efficient immune modulator

– Should be recommended if pharmacological therapy is not efficient or tolerated

• Critical issues for immunomodulators:

– Many options for similar cases

– Optimal treatment goals are not yet accomplished

• Decreased symptoms, exacerbations and improved QOL

• Prevent/alter disease course

• Cost effective

• Favorable risk/benefit ratio Too powerful

Broad-spectrum

Too weak

Very specific

36

The usefulness of component-based diagnosis

Valenta, Nat Rev Imm 2002

Multi-allergen test system

(allergen microarray)

37

Thank you !

Prof. Rudolf Valenta,

MUW

Dr. Eva Wollman,

MUW

Dr. Frank Stolz,

Biomay Viena

Ing. Cristinel Gheorghiu,

Bioclinica Laboratory

Mr. Fernando Pineda de la

Losa

DIATER Spain

induced respiratory allergic diseases

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