By Katrina Sturrock and

Shayalini Wignarajah
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.


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 .

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.



Another method used to assess type 1 hypersensitivity.
Determines serum level of total Ig E (can detect nanomolar levels). Based on the
radioimmunoassay.
Detects the serum level of IgE
specific for a given allergen.
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 .



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- , eosinophilic chemotactic factor and
platelet-activating factor.

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



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.

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.


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
IL4R but IL4R1. The major problem encountered with this
therapy is that IL-4 rapidly degrades in vivo.












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)






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
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)











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 FcRI 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 Fc receptors in the absence of bound antigen.

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

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.

Leukotrienes 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.








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)

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.



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.

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).














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.

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 prevention
of macrophage accumulation leading to a

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.
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.





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.

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- (Kline et al, 2007) .

Induce Th1 response.

However more trials are ongoing to find the proper
mechanisms. .




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.

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)

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





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
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