Memorandum by Research Councils UK
KEY POINTS
1. Allergy is driven by immune mechanisms
that range from acute (short-term) responses that can be potentially
fatal to chronic (long-term) diseases such as asthma, eczema and
rhino-conjunctivitis. The high prevalence and morbidity associated
with these long-term illnesses can inflict a poor quality of life
on sufferers and a high burden to the economy and the health service.
2. RCUK's major contribution to research
into allergy comes in the form of grant funding provided by the
MRC and the Biotechnology and Biological Sciences Research Council
(BBSRC). The MRC currently invests £5.14 million pa on research
and training into allergy and the BBSRC £1.6 million pa.
BBSRC also invests in allergy research via the Institute of Food
Research.
3. In the UK, research into the underlying
mechanisms of allergy and allergic disease is restricted to a
few centres, but most of these groups are world-leaders in their
field. Therefore, whilst research in this area needs to be encouraged,
the existing researchers are of high international standing and
the research funded is of excellent quality.
4. In 2004, the MRC carried out an analysis
of its respiratory research portfolio. It concluded that its research
spend on respiratory diseases, including asthma, was low in relation
to morbidity. The MRC identified respiratory research as a strategically
important priority. As a result of this, and through partnering
relevant charities, the MRC has markedly increased its funding
of research in this area from 6 awards (£0.5 million pa)
to 15 awards (£2.0 million pa). Notwithstanding this, the
UK Clinical Research Collaboration (UKCRC) subsequently identified
that the research spend from all funding bodies on respiratory
diseases, including asthma, is low in relation to morbidity.
5. MRC believes that working with partners will
help tackle the broad challenges posed by allergic diseases. In
addition to the collaborations with charities, the MRC has created
partnerships with Universities in Edinburgh, London and Birmingham,
to create Centres of research excellence into the allergic mechanisms
of disease, inflammation and associated immunological processes.
DEFINING THE
PROBLEM
6. The incidence of allergy in the UK is
high and increasing, for example, more peanut hyper-sensitivity
cases have been reported in the UK suggesting that peanut allergy
is becoming more prevalent. Chronic allergic disease is now common,
affecting 20 per cent of households in the UK. Effective treatments
for allergy are few and can be toxic. This is a driver for an
increased research effort which the RCUK has responded to through
major investments in UK research.
7. From the patient's perspective, allergy
embraces conditions such as rapid sneezing, itching, rash, shortness
of breath, and in its most extreme form, anaphylactic shock,which
can be fatal if not treated quickly. From a research perspective,
the term allergy is used to describe a hypersensitivity that results
from altered or heightened reactivity of the immune system in
response to external or "foreign" substances. These
foreign substances are called allergens and examples include grass
pollen, weed and tree pollens, house dust mites, fungal spores,
animal proteins, certain foods (eg peanuts) and chemicals.
8. Allergens enter the body where they may
come into contact with certain types of white blood cells known
as mast cells and basophils. The allergen binds to a molecule
on these cells known as IgE. [4]Binding
of IgE on these cells causes them to release histamine and other
chemicals stored within the cell. These other chemicals, known
as cytokines and chemokines, attract other types of white blood
cells known as leukocytes to the area. The activation of these
leukocytes, together with the initial activation of mast cells
and basophils, is known as the inflammatory response and this
produces marked changes in the muscles and blood vessels in the
affected area. It is this response that produces the characteristic
symptoms associated with an allergic response. [5]
9. Coupled with this rapid response is the
more, long-term, activation of a different white blood cell known
as the T helper 2 (Th2) cells. The activation of Th2 cells directs
the production of more IgE molecules, produces more cytokines
and chemokines and so attracts more leukocytes. [6]This
chronic response is important in orchestrating the immune system
in allergic disease. Continued activation contributes to the persistent
symptoms of allergy, for example, persistent airflow obstruction,
that requires regular anti-inflammatory treatment often with corticosteroids.
Chronic inflammatory conditions are of most concern as they can
impose on sufferers a low quality of life, a high burden on the
Health Service and a heavy economic impact due to working days
lost.
10. There are also conditions caused by external
substances that stimulate the immune system and Th2 cells without
involving IgE-dependent cell activation. Examples include some
forms of drug allergy, occupational asthma and some types of dermatitis.
The mechanisms of Th2 cell activation in these diseases are unknown.
Some forms of sensitisation, for example, contact dermatitis,
involve a different type of immune response known as the delayed-type
hypersensitivity response.
11. Finally, there are also conditions caused
by external factors such as foodstuffs which are not mediated
by known immunological pathways and are often referred to as intolerances;
these include disorders such as Irritable Bowel Syndrome and migraine.
There are also conditions that are confusingly described as "allergic",
for example Attention Deficit Hyperactivity Disorder, chronic
fatigue syndrome (CFS, ME) and multiple chemical sensitivity syndrome,
where the evidence for an allergic basis is weak.
12. In summary, from a research point of view,
an allergic response can be distinguished from intolerance as
having its basis in an immunological process involving Th2 cell
and (usually) IgE activation. Through complex pathways and mechanisms,
this can lead to a specific type of chronic inflammatory response.
Scientists supported by RCUK are working hard to discover the
mechanisms by which the immune system is activated. This includes
studies of Th2 cells, mast cells and the chemicals these cells
release. Also, why the resulting inflammation can in some cases
continue indefinitely leading to chronic and debilitating disease.
The current state of allergy research might be broadly described
as extensive knowledge about the underlying mechanisms of the
complex pathways that lead to disease, but as yet too few effective
therapies. This is why a focus of MRC research strategy is currently
to translate basic research knowledge into the development of
new prophylactics and cures.
THE BBSRC'S
CONTRIBUTION TO
RESEARCH INTO
ALLERGY AND
INFLAMMATION
13. The Biotechnology and Biological Sciences
Research Council (BBSRC) funds work on allergy through studies
on basic immunology and on food allergies at the Institute of
Food Research. Six relevant projects funded at BBSRC-supported
Institutes in 2005-06, cost £672,935 and in 2006-07, £741,859
was invested in three projects. The Institute of Food Research
will be making a separate submission to the House of Lords Select
Committee.
14. The BBSRC also currently funds University-based
research totalling £193,828, as well as four studentships,
for research training directly relevant to the study of allergy.
In addition, both BBSRC and MRC support a significant amount of
research on basic immunology which may be relevant to the mechanisms
underlying allergic responses.
THE ESRC'S
CONTRIBUTION TO
RESEARCH INTO
ALLERGY AND
INFLAMMATION
15. The Economic and Social Research Council
(ESRC) is the UK's leading research funding and training agency
addressing economic and social concerns. We have an international
reputation both for providing high-quality research on issues
of importance to business, the public sector and government and
for our commitment to training excellence, which produces world-class
social scientists.
16. The ESRC's funding of research into allergy
is less central to our strategic objectives than some other Research
Councils. However, we do fund research addressing an as yet largely
un-explored area of the social implications and consequences of
the rise in allergies, in particular focusing on food allergies
and food intolerance. Very little is known about how lay and professional
people define or explain food allergies and intolerance, how people
live with them, or how those who cater for people's food and health
needs in a variety of institutional settings manage this growing
challenge.
17. In addition, the ESRC funds a wider range
of research relevant to the area including research on the social
contexts of risk and individual and social responses to risk,
genomics and genomic identity, the environment and public understanding
of science.
THE MRC'S
CONTRIBUTION TO
RESEARCH INTO
ALLERGY AND
INFLAMMATION
18. The MRC funds research aimed at improving
human health and has supported some of the most significant discoveries
in medicine in the UK. The Council is committed to funding the
highest quality proposals and has recently increased its investment
in understanding inflammation especially in the respiratory system.
Our current investment in this research is of the order of £
5.1 million pa covering both immunology and inflammation research.
The portfolio is summarised briefly at Annex 1.
19. The MRC's research strategy in this area
is further developed in Annex 2. The MRC believes that forming
partnerships is an important approach to tackling the challenges
posed by allergic diseases as evidenced through MRC partnerships
with Universities to develop Centres of Research Excellence. The
MRC is also partnering Asthma UK, the British Lung Foundation,
the British Thoracic Society and the Morriston Davies Trustees
in funding studentships that will build research capacity in this
area.
RESPONSES TO
SOME HOUSE
OF LORDS
COMMITTEE QUESTIONS
What is allergy? What is the difference between
allergy and intolerance?
20.This has been addressed in paragraphs 6 to
10.
What is and what is not known about the origins
and progression of allergic disease?
21. This is covered in some detail in the Royal
College of Physicians (RCP) Report "Allergy, the unmet need".
There is also an increasing literature on the origins of allergy. For
diseases such as atopic dermatitis (eczema), food allergy and
asthma, it would appear that the onset of the allergic state is
in early childhood, possibly intra-uterine or during the first
few months of life. Sensitisation to specific allergens has a
strong genetic component but the rising trends in allergy worldwide
is likely to be due to changes in the environment (Asher M I et
al, Lancet 2006; 368: 733-43).
22. While exposure to new and/or previously
uncommon allergens, such as peanuts, tropical fruits etc may in
part explain some of the increased allergy seen in childhood,
it does not explain it all (Bioschoff SC, Curr Gastroenterol Rep
2006; 8: 374-82). Considerable interest has been generated in
the role of diet (anti-oxidants, polyunsaturated fatty acids,
unpasteurised milk and probiotic bacteria) and exposure to rural
environments as protective against allergy possibly by programming
the early life response to allergens (Perkin MR, Strachan DP,
J Allergy Clin Immunol 2006; 117: 1,374-81).
23. Prospective studies from pre-conception
to adulthood will be needed to address some of these issues. A
number of human study cohorts already exist; for example, the
MRC together with the Wellcome Trust, is a funder of the Avon
Longitudinal Study of Parents and Children (ALSPAC) and the UK
Biobank, both of which may be resources for such studies. MRC
has contributed £4.5 million over five years toward the ALSPAC
cohort and has committed £28 million for the recruitment
phase of UK Biobank, planned to end in 2010. The MRC, in partnership
with the University of Southampton, also funds the Southampton
Women's Survey. Their aim is to learn more about the dietary and
lifestyle factors that influence the health of women and their
children—including the effect of these on allergies.
What gaps exist in establishing the overall disease
burden for all types of allergy and what are the barriers to filling
these gaps?
24. Three comprehensive enquiries into allergy
and allergy services in the UK have been published. 72[7]
All of these have highlighted the lack of information about individual
diseases and their burden, as well as commenting on service provision
relating to allergy. It is clear that more information is required
in this area so that health economic calculations can be undertaken.
25. It is not appropriate for MRC to comment
on the provision of health services to those suffering from allergic
disorders.
In addition to the impact on the Health Service
what is the overall socio-economic impact of allergic disease?
26. The socio-economic impact of allergy maybe
much greater than is commonly appreciated largely because allergy
rarely occurs in a single organ and manifests through multiple
organs. For example asthma and rhinitis occur together in over
80 per cent of patients with asthma (Demoly P and Bousquet J,
Lancet 2006; 368: 711-3).The combined morbidity imposed by this
multi-organ expression of allergy requires further research. A
second element that needs to be taken into account is the effect
of allergic disease on patients' lives. Recent studies have shown
a large impact of diseases such as asthma, hay fever and atopic
dermatitis on quality of life.
What is the effect of current treatments on the
natural history of allergic disease?
27. It would appear that anti-inflammatory therapy
for diseases such as asthma, rhinitis and atopic dermatitis do
not affect the natural history of these disorders. Specifically,
corticosteroids have a marked suppressive effect on the inflammation
with control of symptoms, but as soon as the steroids are withdrawn
the disease appears again sometimes more aggressively than before.
The only therapy so far that has been shown to influence the natural
history of allergic diseases is immunotherapy, a treatment not
yet extensively used in the United Kingdom due to fears over side
effects, amongst other issues (Frew AJ, Clin Exp Allergy 2006;
36: 251-3). The only other factor that has been shown to influence
the natural history of allergic disease is avoiding contact with
the offending antigen. This is only useful in certain instances,
such as occupational asthma eg that experienced by small animal
handlers. Interestingly, clinical trials have shown that allergen
avoidance in children genetically at risk of asthma, either fails
to influence the development of allergy or leads to even greater
sensitisation (Simpson A & Custovic A, Curr Opin Allergy Clin
Immunol 2004; 4: 45-51). This observation suggests that allergen
reduction strategies in children may remove protective agents
from the domestic setting as well as those leading to sensitisation.
Thus, in summary, apart from limited allergen avoidance and immunotherapy,
there are no current therapies that are known to influence the
natural history of allergic disease or allergy in general.
What is the evidence base for pharmacological
and non-pharmacological management strategies?
28. As stated above, most allergic diseases
are managed by drugs that either treat the symptoms or suppress
inflammation, but they do not influence the natural history of
the disorder. There is evidence to suggest that allergen specific
immunotherapy has beneficial effects on the allergic immune and
inflammatory responses in patients. This involves giving patients
allergens or modified allergens by injection, or more recently,
sub-lingually and has shown promise in allergic rhinoconjunctivitis
and venom allergy. The benefits of this approach have not yet
been tested in large scale clinical trials.
Is the level of UK research in allergy and allergic
disease adequate?
29. It is worth noting firstly that although
research in this field is limited to a few centres, the UK is
a world leader in many specific aspects of research into the underlying
mechanisms of allergy and allergic disease.
30.The UK Clinical Research Collaboration (UKCRC)
analysis[8]
has identified that there is an imbalance in research funding
for all respiratory diseases, including allergic diseases such
as asthma, compared to the severity of disease as measured by
the disability adjusted life years (DALYs). This did not surprise
the MRC who had already issued a Highlight Notice (see Annex 2)
and had started working closely with the British Thoracic Society,
Asthma UK and British Lung Foundation to encourage the respiratory
research community to bid for funding. The added value and agility
of this partnership approach has been successful in stimulating
new interest. The number of applications increased markedly between
April 2005 and March 2006 and the number of awards rose from 6
awards (totalling £0.5m per annum) in 2004 to 15 awards (£2.0
million per annum) in 2006.
What are the most promising areas of research
in preventing or treating allergy?
31. It is important to pursue several avenues
of research to combat allergic disease. The MRC has funded several
research programmes at the forefront of research into allergy,
some of which are at Annex 2. Broadly speaking these can be broken
down to: 1) genetic studies to identify the genes responsible
for allergies, 2) cellular studies to find out more about how
the cells of the immune system function in health and disease
and 3) new treatment evaluations such as oral immunotherapy. Other
avenues of future research include studies into environmental
aspects of allergy such as identifying new allergens, determining
the effect of reducing or increasing allergen exposure on allergy
and the effectiveness of pro-biotics as a treatment for allergic
diseases.
32.Of special interest is the shaping of the
early life immune response towards or away from allergy via pattern
recognition receptors such as Toll-like receptors. Ligands that
stimulate these receptors may have potential preventative and
therapeutic potential. The production of recombinant allergens
that generate protective immune responses without triggering an
allergic reaction is another promising area of research.
33. The following questions posed by the House
of Lords Science and Technology Committee have not been addressed
as they lie outside of the remit of the Research Councils:
Government policies
— How effective have existing Government
policy and advice been in addressing the rise in allergies?
— How is current knowledge about the
causes and management of allergic disease shared within Government?
For example,
— Do housing policy and regulations
governing the indoor environment pay enough attention to allergy?
— How effectively are food policy and
food labelling regulations responding to the rise in food allergies?
Patient and consumer issues
— What impact do allergies have on
the quality of life of those experiencing allergic disease and
their families?
— What can be done to better educate
the public and to improve the quality of information that is available
to patients and undiagnosed sufferers?
— Are current regulatory arrangements,
for example, those governing private clinics offering diagnostic
and therapeutic services and the sale of over the counter allergy
tests, satisfactory?
Annex 1
SUMMARY OF MRC FUNDING IN ALLERGY AND IMMUNOLOGY
ALLERGY
The MRC currently spends £5.14 million
pa on allergy research.
This is comprised of:
£3.15 million for MRC grants to academic
researchers in universities.
£1.44 million for direct support in MRC
Units and Institutes.
£0.55 million for research training.
IMMUNOLOGY RESEARCH
UNDERPINNING RESEARCH
INTO ALLERGY
The MRC currently spends a further £15.3
million pa on research into basic immune function.
This is comprised of:
£5.7 million for MRC grants to academic
researchers in universities.
£7.9 million for direct support in MRC Units
and Institutes.
£1.7 million for research training.
Annex 2
MRC RESEARCH STRATEGY
1. The MRC recently highlighted the need for
more research on respiratory disease—a manifestation of
many allergic and inflammatory diseases by issuing a call for
innovative research proposals. This call highlighted perceived
barriers to progress in this area, such as the need for animal
and/or human models of disease. Such models can be used to study
disease mechanisms and pilot novel therapies. The call also highlighted
the need to perform longitudinal studies to establish aetiology
of disease. As a result, there has been a recent and significant
increase in the MRC portfolio of funded research into allergy
and related conditions of the respiratory system.
2. The commercial arm of MRC, MRC Technology
(MRCT), is sponsoring major "showcase" events in 2007,
on the subject of immunology, infection and inflammation. These
will highlight the work of MRC-funded scientists to members of
the pharmaceutical and biotech industries. It is hoped that this
will increase partnerships between academia and industry and promote
the translation of more basic research into therapy.
3. In November 2005, the MRC participated
in a joint-funded workshop attended by other major stakeholders
(the Wellcome Trust, Department of Health and the major charitable
supporters of respiratory medicine: Asthma UK, the British Lung
Foundation and British Thoracic Society) to encourage research
in the field and identify any tractable barriers to progress.
Several key individuals including the Director of the Wellcome
Trust (Dr Mark Walport), the Department of Health's Director of
R&D (Professor Sally Davies); and the MRC's Chief Executive
(Professor Colin Blakemore) made keynote speeches on their current
portfolios in the area. The 72 participants included senior scientists
and a report has been published on the BTS website. Since this
workshop, the MRC has also been very active in working with the
respiratory charities to encourage high quality applications and
increase the participation of the research community in new funding
initiatives, such as the recent MRC call for funding of Experimental
Medicine.
4. The MRC intends to work closely with the
newly established UK Respiratory Research Strategy Committee.
This Committee has been set up to promote the need for world class
research into respiratory disease. It will produce updates for
research strategy in consultation with its constituent groups
and other outside bodies.
MRC CENTRES OF
EXCELLENCE
5. The MRC funds Centres of Excellence in partnership
with UK Universities. This unique type of funding supports scientific
strategy that links and reinforces existing work as well as fostering
new lines of research. MRC funding for these Centres helps UK
Universities develop and sustain research with a clear strategic
direction in areas of importance for knowledge and health. Allergy
research has benefited from three such centres.
6. The MRC-Asthma UK Centre in Allergic Mechanisms
of Asthma was launched in September 2005. The Centre is funded
by the MRC and Asthma UK with a grant of £0.9 million over
three years and directed by Professor Tak Lee, King's College
London and Professor Tim Williams, Imperial College London. The
three main aims of the Centre are:
(1) to advance the understanding of allergic
mechanisms in order to inform the development of new, effective
and targeted treatments;
(2) provide high-quality, basic and clinical
research training in allergy and asthma; and
(3) provide quality public information on
allergy and asthma in conjunction with stakeholders and partners.
7. The University of Edinburgh/MRC Centre for
Inflammation Research (CIR) was established in 2000 with an MRC
grant of £1.113 million over 5 years and is headed by Professor
Chris Haslett. The Centre comprises 10 major groups and over 150
investigators to pursue co-ordinated interdisciplinary research
into three key control points of inflammatory disease—the
initiation, regulation and resolution of inflammation. The Centre
brings together a critical mass of internationally outstanding
researchers in inflammation harnessing the skills of both basic
and clinical scientists. There is a keen interest in research
training in the molecular cell biology of inflammation, which
has been particularly successful in nurturing young clinical scientists,
adding vital capacity to this research area.
8. The MRC also funds The University of Birmingham/MRC
Centre for Immune Regulation directed by Professor Eric Jenkinson,
contributing £1.5 million over five years. This Centre brings
together 16 internationally regarded research groups, with complementary
skills in studying the different facets of immune responses and
their regulation. It links basic research on immune regulation
with the study of relapsing and remitting inflammatory conditions
associated with immunological damage to joints or blood vessels.
OTHER EXAMPLES
OF MRC-FUNDED
RESEARCH
9. The MRC has a well established commitment
through intramural funding for research into allergy. Professor
Sir Philip Cohen Director of the MRC Protein Phosphorylation Unit
in Dundee, is a world expert on the intracellular mechanisms involved
in immune- and inflammatory-cell activation. The steps involved
in this activation may offer new targets for drug interventions
to prevent allergic disease. Professor Dan Cutler in the MRC Cell
Biology Unit, London has been investigating the mechanisms by
which white blood cells move from the blood vessels towards sites
of inflammation and specific targets that can be attacked to prevent
inflammation. Dr David Jackson from the MRC Human Immunology Unit,
Oxford has been studying blood cell trafficking in inflammation
and how these cells are controlled by the proteins released during
inflammation. They have discovered that during inflammation, some
white blood cells will actively bind inflammatory proteins and
so cause their own activation.
10.The MRC also funds a number of novel, cutting
edge programmes of research looking at inflammatory mechanisms
in the lung. For example, MRC Professor Stephen Holgate and his
team from the University of Southampton have been studying the
cells lining the airways of the lungs and have shown that in asthmatics,
these cells are more susceptible to injury. They have also shown
that levels of a powerful immune system chemical, tumour necrosis
factor (TNF) are much higher in the lungs of people with severe
asthma compared to non-asthmatics. This raises the question as
to whether drugs that TNF would be an effective treatment for
asthma and the Southampton team are carrying out these studies.
11. IgE-dependent mechanisms in allergic diseases
such as asthma are clearly of fundamental importance in our understanding
these diseases. The MRC is funding research at Kings College London
led by Professors Brian Sutton and Christopher Corrigan to study
the structures of these molecules and their receptors. Based upon
these structural studies, they are designing small molecules to
inhibit receptor interactions and control the allergic response.
6 October 2006
4 Allergens enter the body by inhalation, injection
or through contact with food. They bind to specific IgE which
itself is bound to high affinity receptors (FcsR1) on the surface
of mast cells and basophils. There also exists a low affinity
IgE receptor (FcER2) but its role is unknown. Back
5
Symptoms differ depending upon the target tissue eg in asthma-contraction
of smooth muscle causes bronchoconstriction and wheezing. In allergic
rhinitis-nerve stimulation, vascular swelling and mucus secretion
cause sneezing, rhinorrhoea and nasal obstruction. In anaphylaxis,
systemic activation of mast cells and basophils causes massive
release of mediators into the circulation leading to cardiovascular
failure. Back
6
Th2 lymphocytes initiate isotype switching of B lymphocytes to
IgE synthesis, augmenting recruitment of secondary leukocytes
such as eosinophiis through the secretion of specific cytokines
eg interleukins (IL) ¸4, ¸5, ¸13 and GM-CSF and
chemokines eg the eotaxins and RANTES. Back
7
The Royal College of Physicians Report, 2003 "Allergy the
unmet need"; House of Health Committee "The Provision
of Allergy Services" Sixth Report of Session 2003-04; The
NHS Enquiry, 2006 "A review of services for allergy-the epidemiology,
demand for and provision of treatment and effectiveness of clinical
interventions". Back
8
(http://www.ukcrc.ora/PDF/UKCRC Health Research Analysis Report.pdf). Back
| 
