Asthma & Allergy

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The role of Immunotherapy in the treatment of Asthma & Allergy, its pathogenesis and diagnosis By Katrina Sturrock and Shayalini Wignarajah

Transcript of Asthma & Allergy

Page 1: Asthma & Allergy

The role of Immunotherapy in the treatment of Asthma

& Allergy, its pathogenesis and

diagnosisBy Katrina Sturrock and Shayalini Wignarajah

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What is an allergy An over-reaction of immune system to a non –harmful stimuli . Antigens

provoking such a response are known as allergens .

This can lead to deleterious effects -results in tissue injury , serious disease or even death. This develops in course of either humoral or a cell- mediated immune response.

P.G.H Gell and R.R.A Coombs in 1963 , proposed a classification scheme where the hypersensitivity reaction are divided into 4 types:

Type 1 – Ig E mediated hypersensitivity. Type 2 – Antibody (Ig G and Ig M) mediated cytotoxic hypersensitivity .

Type 3 – Immune complex –mediated hypersensitivity . Type 4 – Cell mediated hypersensitivity (delayed type).

Each type of hypersensitivity consists of distinct immune mechanism, cells and mediator molecules.

Many reports have suggested , there is an association between genes that exert their effects predominantly in combination with environmental factors, e.g., cigarette smoke (Kabesch, 2006) to cause allergies.

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Type I Hypersensitivity Pathogenesis

Type 1 Hypersensitvity induces the humoral immune response.

Involves IgE , mast cells , blood basophils , eosinophil's,

Th2 cells produce cytokines like interleukins such as, IL-4 and IL 13 that enhance production of specific IgE antibodies by B cells and result in hypersensitivity, eosinophil activation, mucus production and IgE secretion. (Drouin et al. 2001).

IL -5 induces the production of eosinophils , which causes over-production of the mucus.

Active mediators such as histamine and leukotrienes are released from the mast cell granules and they act on the surrounding tissue.

The principal effects are vasodilation and smooth muscle contraction, maybe either systemic or localized depending on the extent of mediators released.

Response is very rapid .

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Tests used to detect allergies

Skin testing also known as - common used for type 1 hypersensitive individuals .

Small amounts of allergens introduced at specific skin site , either by superficial scratching or by intradermal injection.

The allergen are applied on the forearm or back of an individual at one time.

If the individual is allergic to the allergen , the local mast cells degranulate and the release of histmaines and other mediators produce a wheal and flare within 30 minutes.

In late- phase reaction – eosinophils become accumulated, and this causes the release of eosinophil- granule contents which can lead to tissue damage.

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Radiommunosorbent Test

Another method used to assess type 1 hypersensitivity.Determines serum level of total Ig E (can detect nanomolar levels). Based on the radioimmunoassay.

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Radioallergosorbent test

Detects the serum level of IgE specific for a given allergen.

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What is Asthma? Chronic inflammatory disorder of respiratory airways

characterized by increased mucus production and airway hyper-responsiveness. ( A.L. ,Miller ,2001)

Also characterized by bronchial airway inflammation. This results in decreased air flow recurrent episodes

of wheezing, coughing and shortness of breath. Associated with genetic allergic and environmental

factors. Millions over the world suffer from this. Childhood asthma is linked with family history of

allergies. According to the NHS , 5.4 million of people suffer

from asthma in the UK .

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The pathogenesis of Asthma Inflammatory response can be acute, sub-acute or chronic.

Airborne or blood borne allergens , such as pollen, dust ,fumes , insect products or viral antigens trigger an asthmatic attack.

Eosinophils, neutrophils, and Th2 cells can be recruited, and Ig E synthesis and mast cell initiation.

Can be triggered by degranulation of mast cells with release of mediators such as histamine, prostaglandins and leukotrienes. This occurs within minutes.

Late response asthma occurs hours and involve additional mediators, including IL-4 , IL-5 , IL-6 , TNF-α , eosinophilic chemotactic factor and platelet-activating factor.

Damage to the epithelium leaves the bronchioles hyperresponsive, with bronchoconstriction following many chemicals or irritants. .

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C-Reactive Protein Produced by the liver and belongs to a family called the

pentraxins, it is an important opsonin in activating the complement pathway. Male, D. et al (2006)

Rapidly synthesized in response to synthesis of IL-6 Marshall, W. et al. (2008)

Elevated after the precipitation of an acute phase response

The plasma concentration of CRP begins to rise 6 hours after the onset of inflammation occurs

C reactive protein is a non specific plasma protein marker, however if there is a known exacerbation of asthma, it is useful to monitor blood serum CRP levels to monitor the remittance of inflammation.

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There are disadvantages to the use of peptide desensitization:

It is unknown whether only incomplete stimulation of the T cells can provide an effective tolerance to the specific allergen

It is unknown whether a change in the cytokine profile occurs (Male, D. et al. (2006)

There are significant interaction's within the lung causing a fall in FEV1- potentially fatal in asthmatic patients with an already compromised maximal forced expiratory volume. Agbatile, J. et al (2010)

Multiple peptides would be necessary to incorporate presentation of antigen in patients with different HLA complexes.

Disadvantages of using peptide immunotherapy

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Cytokines: a role in immunotherapy

Cytokines are inflammatory mediators released in response to allergens in conditions such as asthma and allergic responses such as that to pollen in allergic rhinitis and anaphylaxis.

Current forms of therapy of cytokine inhibition experimentally is upon IL-4, IL-5 and IL-13.

IL4 has a role in both Th2 differentiation and the synthesis of IgE. Anti IL-4 blocking antibodies have been used on experimental models and were demonstrated to block allergen induced airway hypersensitivity, goblet cell metaplasia and lung eosinophilia. Hans-Uwe, S. (2006)

A mutated form of IL-4 has being encountered which can act as a competitive inhibitor of both IL-4 and IL-13. The cytokine IL-13 is blocked due to mutated IL-4 not only binding to and blocking IL4Rα but IL4Rα1. The major problem encountered with this therapy is that IL-4 rapidly degrades in vivo.

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Studies upon mice demonstrated the implication of IL-13 and its role in asthma and its exacerbation. Features include, airway hyper responsiveness , mucous hyper-secretion, eosinophilia and airway remodelling.

As well as cytokine therapy upon IL-13 via the competitive inhibition of IL-4, there is also experimental assays surrounding the use of the soluble IL-13 receptor which has a higher affinity for IL-13, and higher efficacy than through IL-4. The blockage of IL-13 is a fascinating area for progressive research as a new method for treating asthma. Currently, a humanized soluble IL-13 receptor is under development for the use of treating asthma. Borish, L. et al. (2010)

IL-5 is a survival factor and involved in eosinophil differentiation. Blocking IL-5 suppressed eosinophilic induced inflammation and AHR in several experimental asthma models. This may be further developed as a treatment, but as a combined therapy as it targets only one aspect in the pathophysiology of asthma. Kay, A. (2006)

Cytokines as therapeutics

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IgE & its role in atopic asthma In allergic asthma, when the asthmatic inhales an allergen which they

are allergic to, the immune response is to release IgE. On further presentation of the allergen on a secondary occasion, the

immune system is primed via IgE recognition, and reacts rapidly and aggressively to the harmless allergen. (Male, D. et al. (2006)

IgE attaches to the mast cell via binding to its receptor, the light chains of IgE then attach to the allergen and they bind together. When the equivalence point between allergen and IgE is reached, the mast cells decompose releasing inflammatory mediators such as histamine and leukotrienes into circulation. Ryan, J. et al (2009)

It is the release of inflammatory mediators such as histamine which leads to airway inflammation and produces symptoms such as shortness of breath, wheezing and tightness in the chest characteristic of asthma

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Xolair, a wonder cure for asthma?

A novel new mode of therapy targeted towards asthma, involves monoclonal antibodies to directly target IgE receptors. Via reducing sensitivity to the receptors, humanized monoclonal anti-IgE treatment can thus significantly decrease the number of acute asthmatic episodes per year.

This therapy is only suitable for patients with identified IgE mediated asthma. (Holgate, S. et al (2005)

IgE is a mediator in most allergic reactions and those with atopic asthma may benefit from the use of Xolair - a drug licensed in October 2005 by EMEA to target IgE mediated asthmatics.

Xolair was created via creating a humanized mouse monoclonal antibody to IgE, and can be injected safely into a patient with a very high binding affinity to IgE. (Xolair patient safety sheet)

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The mode of action of Xolair The mode of action of Xolair is to bind to the IgE receptors preventing them from attaching to the mast cells and being stimulated by the allergen.

Effector cells are engaged by antibodies, via binding to receptor, specific for the FC constant region of an antibody. Antibodies can be directed against the binding site for FcεRI on IgE and can bind to IgE in circulation.

Antibodies engage the effector cells via binding to the receptors specific for the Fc constant region of the antibody. Most antibodies engage Fc receptors only after the variable regions have bound to a specific antigen, however IgE is an exception as it is captured by high affinity Fcε receptors in the absence of bound antigen.

Therefore unlike other antibodies, IgE is found fixed within the tissues on mast cells bearing this receptor.

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The future of Xolair Symptoms of both asthma and hay-fever were shown to be clinically

reduced via treatment with IgE monoclonal antibodies. It was also demonstrated clinically that continued treatment which

maintains free IgE below 10ng/ml leads to a progressive decrease in the number of IgE receptors present on mast cells. Esteitie, R. et al (2010)

However a trial was conducted using Omalizumab to treat those with IGE mediated atopic dermatitis. After 4 months of subcutaneous injection with Omalizumab, no improvement was seen in any patients taking part in the trial. This was however particularly limited on only 3 subjects. (Krathen et al 2005)

It is hoped that the future of anti-IgE can be further evolved to be used in patients with allergies including those to latex, food allergy and perhaps the most lucrative- drug allergies.

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Leukotriene antagonists & the role of Montelukast

Leukotriene’s add to the pathogenesis of asthma via potentiating symptoms such as: Airflow obstruction Increased secretions and

accumulation of mucus Bronchoconstriction Infiltration of inflammatory

cells in the airways

Leukotriene's are inflammatory molecules released from mast cells during an asthma attack. This is an example of an acute consequence of asthma- an attack.

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What do leukotriene's do?In severe chronic asthmatics, eosinophil's are primarily responsible for bronchoconstriction, eosinophil's are attracted into the bronchioles via leukotriene's and other chemo-attractants such as histamine. Leukotriene's have a role in both chronic asthma and acute attacks.

Montelukast works upon the Cysteinyl leukotriene receptors identified as CysLT1 and CysLT2 Leukotriene's are a moiety of arachidonic acid within the body via an enzyme classified as enzyme 5-lipoxygenase. (McRae, M, et al. 2011)

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Mechanism of action of Montelukast

The CysLT1 & CysLT2 receptors are present on mast cells, eosinophil's and endothelial cells and are primarily associated with mast cell induced bronchospasm.

During leukotriene interaction, they are able to stimulate pro-inflammatory activities such as chemokine production from the mast cells. Due to their inflammatory mediation, they are able to induce asthma symptoms restricting air entry and gaseous exchange over the alveoli.

Montelukast functions via inflicting its mode of action upon CysLT1 receptors, the drug selectively antagonizes leukotriene D4 (LTD4) upon the receptor CysLT1. Albini, A. et al (2006)

Via inhibiting the action of CysLT1, Montelukast prevents airway oedema, the secretion and accumulation of mucous and smooth muscle construction typical of bronchoconstriction.

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The Future of Leukotriene antagonists

When used in conjunction with antihistamines such as Cetirizine Hydrochloride in treatment of allergic rhinitis, the combined therapy has the same effect as steroidal nasal sprays such as Flixonase. (Esteitie, R. et al., 2010)

There is a trial due to commence whereby researchers aim to identify whether Montelukast would be a suitable therapy in the treatment of atopic dermatitis. (Yan Pyun, B. et al. 2010)

It has been noted that Montelukast has been approved for use in treating allergic rhinitis, however as an adjunct therapy to standard antihistamines as oppose to use alone.

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Antihistamines

Medication used for individuals who have an upper respiratory allergy (asthma).

There is the first generation drug which is chlorphenamine and second generation drug which is Loratadine .

Anti-histamine block the H1 receptor on Histamine.

Prevents release of histamine.

Prevents action of mast cells and basophil (Leurs et al., 2002).

Reduces allergen-induced eosinophils accumulation (Leurs et al., 2002).

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Future Work for Antihistamines

H4 R are new histamine receptor that was currently found.

H4 R antagonists have proven to work in animal models , to treat asthma and allergies. (Engelhardt et al , 2009).

However Clinical trials are ongoing.

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Glucocorticosteroid use in asthma: Prednisolone

reduction of capillary permeability reducing airway oedema and mucous accumulation.Prednisolone inflicts its mode of action via binding to the glucocorticoid receptor upon membranes of

mast cells and eosinophil's with high affinity. Barnes, P. et al. (1998)

Prednisolone is often the steroid of use in treating acute exacerbations of asthma symptoms in the absence of relief from standard preventative drugs and short acting b-2-agonist therapy. Robinson, D. et al. (1993)

It has been heavily debated as to how prednisolone reduces inflammation, some thought it was due to genetic factors such as transcription alteration or causing dysfunctional protein synthesis. Others assumed a preventionof macrophage accumulation leading to a

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Prednisolone: potential immune system dampener??

The long acting preventative therapy- a Fluticasone Propionate inhaler works in the same way as Prednisoloone and is classes as a synthetic glucocorticoid.

In the treatment of asthma, the steroid Prednisolone has the role of down regulating pro-inflammatory mediators including IL1,3 and 5. Thompson, E. et al (2004)

It is also thought to interfere with the biosynthesis of pro-inflammatory molecules such as prostaglandins and leukotriene's.

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DNA vaccine for Allergies Holds promise in the treatment of allergic diseases.

DNA vaccines can be used to reduce allergic reactions. DNA vaccines can be developed by one of three approaches:

(i) using the naked DNA of allergens

(ii) using hypoallergenic derivatives of allergen DNAs by modification of nucleotides

(iii) fragmenting allergen DNA and fusing with ubiquitin, as fragmenting the antigen destroys its native structure. (Weiss et al. ,2003)

Induces Th 1 properties.

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DNA vaccines (cont) Conjugation of allergen to immunostimulatory bacterial

DNA .

Combination of CpG( cytosine-phosporous-guanine) and DNA vaccination is more effective.

Acts as antogonists to Th2 responses.

CpG motif activates APC and NK cells .

Inhibit Ig E production.

Promote Th1 functions.

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Future of DNA Vaccines New Treatment of asthma using DNA vaccines. Combination of CpG (cytosine-phosporous-guanine) and

oligodeoxynucleotides (ODN) with DNA vaccination is a novel therapeutic agent for asthma (Kline et al., 2007).

CpG ODNs reduced airway easinophilic inflammation, bronchial hyperactivity and serum levels of specific IgE and Th2 cytokine response in vivo (Kline et al., 2007).

Also suppress the bronchoalveolar lavage levels of IL-4 , and this increases the levels of IL-12 and IFN-γ (Kline et al, 2007) .

Induce Th1 response. However more trials are ongoing to find the proper mechanisms. .

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Adjuvant therapy Adjuvants attached to allergen molecules are designed to shift the

immune response from TH 2 towards TH1.

Possible co-molecules that act like an adjuvant include:- Cytokines , IL-12; or - Immunostimulatory sequences (ISS)

ISS are DNA sequences such as cytosine phosphoguanidine (CpG) that are common in bacterial DNA .

Immunization with allergen and CpG may produce a greater immune response with less potential for an acute allergic reaction.

Preliminary trials in allergic individuals using ragweed antigen linked to CpG have been successful.

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Future Research A lot of current research surrounding asthma focuses on

experimental models to assay nitric oxide and its role in precipitating asthmatic symptoms and efficacy of treatment

NO is inducible from oxidative stress, it is thought mast cell degranulation has an integral role in mediating oxidative stress and releasing NO on degranulation

Researchers have established a correlation showing that children diagnosed with asthma have increased levels of FeNO, even more so if their parents were not phenotypically asthmatic (Bastain, T et al 2004)

Furthermore the results from a clinical trial conducted at the Royal Brompton is due to be published this October, they are using a portable Nitric oxide monitor to determine any relationship between increasing NO levels and asthma exacerbation and severity. (Chung, K F et al 2011)

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Summary Hypersensitivity reaction are based on the classification of Coombs and Gell. IgE is distinct from other immunoglobulins. Allergens are antigens that give rise to hypersensitivity type 1 and asthma. Skin test, RIST and RAST are used to detect allergies. Asthma is an atopic disease. FEV 1 used to test asthma patients. There are many therapies for asthma and allergies . Immune therapy – Peptides from the primary sequence of an allergen that can

stimulate T cells. Immunotherapy using cytokines – inhibiting cytokine acivity. Xolair- Uses monoclonal antibody to inhibit IgE production. Montelukast inbits the activity of leukotriene D4. Antihistamine – Inhibts the activity of H1 receptors of histamine. DNA vaccines- new method of shifting the immune response to Th1 system,

using bacterial DNA. Adjuvant – attaches to the allergen and shifts the immune response to Th1 . Glucocorticosteroid- interfere with the synthesis of pro-inflammatory. Future treatment – Nitric oxide

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Summary One form of immunotherapy for the treatment of asthma and allergy arises from

specific peptide immunotherapy.

Cytokines have a vast role in inflammatory conditions such as asthma and allergy, by blocking the receptors for cytokines such as IL-4, 5 and 13, there may be a clinical improvement in ones symptoms.

The use of monoclonal antibodies such as IgE have shown to provide relief from symptoms with IgE mediated asthma.

Leukotrienes are an efficient adjunct therapy to standard inhaled corticosteroids

Gluco-corticosteroids are efficient at reducing inflammation in acute exaccerbations of chronic asthmatics

Future research into NO levels amongst sufferers can provide a non invasive insight to possible deterioration of the airways in asthmatics or in the future, possibly identify ‘at risk’ individuals.

Preventative SIT treatment may the future area of research whereby de-sensitizing a patient to an allergen can have an advantageous clinical impact upon another.

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References Langmack. E, Richard. M, (2010) Heterogeneity of response to asthma controller therapy:

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Chung. K, F, Saito, J. (2011) A study to assess the clinical efficacy of the portable exhaled nitric oxide analyzer (FeNO NObreath®) in monitoring asthma control and predicting asthma exacerbation. Pending publication

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