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The Food Allergen Cellular Test (FACT)

by Nigel Abraham(more info)

listed in allergy testing, originally published in issue 29 - June 1998

When triggered in vitro by food allergens to which a subject is sensitive, sensitised blood leukocytes release a range of chemical mediators, notably histamine and a group of chemicals known as leukotrienes (LTC4, LTD4, LTE4). Such mediators are in themselves partly responsible for a number of the symptoms associated with the allergic response. An assay has been developed by Individual WellBeing Diagnostic Laboratories in which the reaction of leukocytes to various food allergens – in a diluted whole blood sample where the leukocytes have been artificially concentrated – can be assessed, especially when the reactive cells have been preincubated for a short period with a priming cytokine (IL3, IL5). The assay utilises a unique monoclonal antibody incorporated into a very sensitive ELISA assay, to measure Leukotriene release precisely.

The test is therefore theoretically capable of detecting a wide range of reactions known to be involved in both immediate and delayed type allergic responses, which are both IgE dependent and independent.

Detection of Food Allergy

As long as a century ago, it was appreciated that exposure of an allergic individual to an antigen produced an immediate response, followed by a later reaction. Recently, this late reaction has been under active investigation and has lead to an even greater confusion over the terminology for such reactions in that they are clearly a form of allergy, which would cover also some forms of food intolerance and food sensitivity. In humans, this reaction can happen within 3 – 48 hours and is characterised by a number of symptoms, including oedema and erythema in the skin, increased resistance to air flow in the nose and lungs, inflammatory reactions involving the joints and muscles, lethargy/ chronic fatigue and gastrointestinal dysfunction classically termed “irritable bowel syndrome”. There have also been a number of well-documented cases linking such reactions with behavioural changes ranging from hyperactivity to links with juvenile crime.

The pathogenesis of this late reaction is complex and not well understood, but the initial event in the human response to an allergen is probably mast cell degranulation with the subsequent release of mediators which, in turn, attract inflammatory cells and upregulate adhesion molecules and other cellular responses.

Using in vivo models of intranasal allergen challenge, it has been demonstrated that such mediators are elevated in nasal lavages when symptoms are present in those individuals experiencing a late phase reaction. Recent studies have also demonstrated a similar effect in the gastrointestinal tract, by a method of direct mucosal challenge showing a classic weal and flare reaction.

Laboratory parameters indicating such food allergy reactions have always been unreliable as a predictive tool. Negative skin tests and an absence of specific serum IgE against food proteins have traditionally confirmed the absence of IgE-mediated reactions, but the positive predictive accuracy of these tests is low. The clinical value of these tests is further limited by the fact that IgE-mediated sensitivity is frequently not detected with commercially prepared reagents, because of the lability of the responsible allergen. In the oral allergy syndromes for example, an individual experiences an immediate type response, usually localised to the lips, mouth and upper respiratory tract, to fresh allergen triggers in some fruits, nuts and pulses. Moreover, it has been suggested in several studies that IgE does not necessarily mediate allergic reactions to food.

Which type of allergy?

The following table is intended as a aid to explain the difference between these two types of allergy.

Immediate Acute Type Allergy

1   TEST Acute allergy screen for IgE specific allergens. Either inhalants, foods or combined screen.

2   IgE antibody mediated (Type1) allergic reaction. usually appears first in early childhood, often continues into adulthood, although the allergy may change.


3
    1 or 2 foods usually involved in causing allergic symptoms.


4
    As a rule allergic symptoms appear in less than 1 to 2 hours after eating an offending food.

5    Common in children, rarer in adults.


6
    Primarily digestive tract, skin, and airways affected. Classically Asthma, Rhinitis, Conjunctivitis and Urticaria.


7
    Except in younger children, this can be self diagnosed.


8
    Can involve rarely eaten foods.

9    Rarely involves addictive cravings or withdrawal symptoms.

10    Small amounts of food can trigger intense allergic reactions.

11    Often a permanent, fixed allergy to a particular food.

12    Frequently skin test and/or IgE blood test positive.
Delayed Allergy/Intolerance

1   TEST Food allergen cellular test F.A.C.T. Including nutritional programme and counselling.

2    Involves a number of different reactions, that are cellular in nature, they may or may not involve IgE and IgG antibodies or direct activation of white blood cells.

3    3 to 15 foods often involveed, 20 – 30 foods in some rarer cases, have been seen.

4    Allergic symptoms appear up to 72 hours after eating.


5
    Very common in adults, virtually every person has some degree of sensitivity.

6    A very wide variety of symptoms involved, including stomach/digestive, head, skin, joints & muscles, weight, energy and emotions.

7    Rarely self diagnosed in any age group, due to vagueness of symptoms and time delay.

8    Involves frequently eaten foods.

9    Commonly involves addictive cravings and withdrawal symptoms.

10    Larger amounts of foods are commonly needed to cause a reaction.

11    Allergic reactions commonly clear following 3–6 months of avoidance.

12    Skin test and IgE blood test often negative.

 

The Food Allergen Cellular Test (FACT)

Now, however, the Individual Wellbeing Diagnostic Laboratory in London has produced the F.A.C.Test, which identifies those foods to which the patient has an allergic reaction by the following method.

Firstly the leukocytes are concentrated by a centrifugation technique to increase the sensitivity of the test. This concentrated whole blood sample is then simultaneously incubated with a ‘priming’ agent and the panel of test food allergens.

The ‘priming’ agent used is a mixture of interleukins IL-3, IL-5; these are naturally occurring cytokines produced by certain leukocytes and have a variety of effects on many cells. Studies have shown that cells, such as mast cells, become far more sensitive to allergen stimulation after such ‘priming’, producing increased, and therefore more detectable, levels of mediator release.

These ‘primed’ leukocytes are then incubated at body temperature (37°C), with a comprehensive range of 154 foods and food additives. During this incubation the cells will react with any food to which they are sensitive, causing the release into the surrounding fluid of the chemical mediators responsible for food sensitivities.

A vital part of the test is the quality of the test allergens used. These allergens are specifically prepared for this type of testing, are made to resemble as closely as possible the natural food product, and contain no additional compounds that may cause a false positive effect on the test cells.

The final part of the test is to assay for the presence in the surrounding fluid of the released mediators. This is performed by using a very sensitive technique called an Enzyme-Linked Immunosorbent assay (ELISA). This type of technique is based on the use of a unique monoclonal antibody that is able to recognise one of the mediator types – namely the leukotrienes.

By a complex system of antibodies and enzymes, the exact quantity of such leukotrienes released is inversely proportional to the degree of a coloured end product. By accurately measuring the amount of colour produced against a standard curve of known amounts of leukotriene, computer analysis indicates not only to which foods the cells are sensitive, but also to what degree.

As with any laboratory result, interpretation is essential. This laboratory, unlike others, employs two fully qualified nutritionists. Every result produced is followed by a detailed nutritional report and one to one nutritional counselling. This is particularly important when treating patients suffering from multiple allergies or young children.

Food Allergy Sensitivity

The incidence of IgE specific antibodies directed to food allergens has been recorded at 30%, considerably in excess of most reported incidence rates. There are a number of possible explanations for this.

Firstly the population analysed was not a general population but that of a selected group who all exhibit symptoms related to atopic allergy. This, however, would still demonstrate the importance of classical food allergy in a number of conditions – notably Irritable Bowel Syndrome and skin disorders such as eczema.

Secondly, the majority of such IgE reactions were classed as grade 1, which is considered a borderline reaction and rarely correlates with the patient’s symptom history and cellular analysis results, suggesting that these results do not represent true atopic allergy.

Thirdly, in a great many cases the presence of such specific antibodies is directed at the classical childhood food allergies of nuts, wheat, cows milk and Soya. However, their adult history does not demonstrate reactions upon challenge and again cellular analysis is often negative. The accurate measurement of IgE specific antibodies is of undoubted value and should be far more widely available to individuals with an appropriate history. However, evidence strongly suggests that the results must be taken in conjunction with patient history and direct cellular stimulation results such as the F.A.C.Test, in order to identify the major reactive food groups.

The patients’ groups which were analysed by the F.A.C.Test and followed a 4-day food rotation programme, based on the results for a 3 month period, produced some extremely pleasing and significant outcomes for most of the symptoms reported at the initial consultation. The percentage improvement, as assessed by independent consultation and the individual’s own perception, ranged from 75% for sinus/rhinitis to 97% for fatigue and general lack of energy. The figure of 93% for Irritable Bowel Syndrome is one of the highest reported, and clearly demonstrates the extremely significant role that such food reactions play in this condition. This has always been accepted by much of the nutritional community, but often disputed by the medical community including many gastroenterologists. This has resulted from the lack of credible studies based on scientifically developed testing systems.

One criticism which is often levelled at such studies is that much of the perceived improvements are because of the placebo effect. There is undoubtedly an element of this in all such studies as it is impossible to give nutritional advice and eating programmes without inevitably improving an individual’s basic dietary intake. However, many of the individuals involved were openly sceptical at the initial consultation and in a number of cases they had had previous such tests and eating programmes by alternative methods and were largely convinced that they would not demonstrate any improvement. It is unlikely that a placebo effect could account for such a high percentage improvement rate. It can also be argued that in the case of Irritable Bowel Syndrome many of the individuals have had the condition for some time and had undergone a wide variety of treatments and tests with little or no improvement. So even in the statistically unlikely event that the whole effect was a placebo, the patients still demonstrated an improvement, which, in the majority of cases, was sustainable, and the intended outcome.

An analysis of specific IgG level revealed similar patterns to that of IgE, in that the presence of IgG class antibodies agreed more closely with the presence of IgG than by F.A.C.T analysis. This demonstrates the limitation of IgG analysis alone for the identification of food sensitivity,  in that in excess of 90% of individuals  tested had significant levels of IgG class antibodies to cow’s milk and egg white, with less than 40% of individuals demonstrating a clinical reaction to these allergens. These results, whilst they are reproducible, fail to give a reliable indication of an individual’s current reactivity to such stimulants.

A number of previous studies have also reported similar success rates. In most cases they have been based on a normal group of individuals who did not have any recognisable medical condition, such as sports teams etc. The groups were also not investigated for other allergy-related parameters. The validity of such studies is therefore debatable as they have often concentrated on aspects such as weight loss, which, whilst it does appear to be a significant side effect in a great many cases, should not be the primary concern for such studies.

Candida albicans

The presence of both IgG and IgM class antibodies to Candida albicans in 50% of individuals tested has confirmed yet again that the importance of Candida in the aetiology of a number of symptoms cannot be underestimated. In virtually all cases the presence of such antibodies correlated extremely well with the presence of related symptoms which were often of a chronic long-term nature. The combination of nutritional guidance to follow an anti-Candida diet and commercial supplements brought a positive response in the reduction of symptoms in approximately 80% of cases. However, follow-up studies showed that whilst the IgM class antibody levels dropped to become negative the IgG levels remained elevated in all cases, and in a few cases the levels actually rose significantly before an improvement was noted. Care should be exercised therefore in the interpretation of the results and patient history is also important. Wherever possible, tests should be performed on more than one occasion not only to confirm the diagnosis but also to gain information about the cause of the condition.

Summary

It is not just a coincidence that the first new generation of Asthma drugs in 20 years, which have been recently introduced, have an anti-leukotriene action both modifying their action and blocking receptor function. It is clear that these mediators in particular are an extremely important factor in the aetiology of an allergic response. The same factors that induce an asthma reaction i.e. broncoconstriction and vessel permeability are the same factors that produce a reaction in other parts of the body, notably the gut. It seems logical, therefore, that the most appropriate method of detecting the triggers for such reaction should be a functional assessment of leukotriene release. The F.A.C.Test is such an assay which has proved extremely valuable in the assessment of an individual’s food triggers. The figures for improvement of allergy related symptoms over a two-year period are in excess of all the more traditional treatments, and in the vast majority of cases can be achieved without drug intervention – indeed such treatments often serve to exacerbate the condition. Longer-term follow-up has also indicated that patients are able to reintroduce sensitive foods after six months in a controlled manner without adverse effects. It must be stressed, however, that from the reintroduction phase 2 studies, this is not always the case with all food types. It is vital that this be supervised by an experienced practitioner with additional F.A.C.T analysis.

The results of this study seem to confirm that the combination of the F.A.C.Test and other laboratory parameters in conjunction with a nutritional assessment seems to be the way forward for the non-invasive treatment of a number of medical conditions, notably IBS. The continuing development of this type of assay will in due course prove similarly useful in identifying inhalant allergy and asthma triggers, which has been confirmed by preliminary data.


Glossary of Terms

Antibodies Serum globulins (proteins) with a wide range of specificity for different antigens, antibodies can bind to and neutralise pathogens such as bacteria, viruses, and parasites as well as inappropriately in allergy and certain diseases (autoimmunity).
Cytokines A large family of molecules produced by various cells of the immune system considered as ‘cellular hormones’ with the ability to regulate virtually every function of the immune system, good and bad. They also communicate with other systems of the body, such as the nervous and hormone systems creating a giant and complex network.
Hypersensitivity Often the result of specific memory caused by re-exposure to the same stimulus, where instead of eliminating the stimulus, it results in unpleasant or damaging effects on the body’s own tissues.
Ig Abbreviation for immunoglobulins.
IgA The major antibody of secretions such as tears, sweat and the contents of lungs, gut urine etc., where it can avoid digestion. Its main function is to block the entry of micro-organisms from external surfaces to the tissues.
IgD Appears to function only on the surface of immune cells called B cells, where it is involved in recognition of foreign antigens.
IgE: Class of immunoglobulin which binds to mast cells and promotes their degranulation. Involved in allergic reactions such as hayfever hives, asthma and anaphylaxis.
IgG The largest class of antibody present in humans. It is speculated that an individual has an antibody that is specific to every possible pathogen or stimulus. This class has further diversified into subclasses i.e. IgG1, 2, 3 & 4.
IgM The first class of antibody made in a response; thought to have been the first to appear during evolution.
Interleukins One of the cytokine families, released by cells of the immune system to affect other cells. One example is Interleukin -3 (IL-3), which can upregulate the reactivity of certain cells of the immune system.
Leukotrienes (LTs) and Prostaglandins (PGs): Family of unsaturated fatty acids derived by metabolism of arachidonic acid. Individual PGs and LTs have different but overlapping effects; together they are responsible for the induction of pain, fever, vascular permeability and chemotaxis of other immune cells, leading to many of the symptoms associated with allergy.
Mast cells A large tissue cell with basophilic granules containing vasoactive amines and compounds such as leukotrienes. It degranulates readily in response to injury by trauma, heat, UV light etc. as well as in allergic conditions.

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About Nigel Abraham

Nigel Abraham MSc. FIBMS has more than 10 years experience as an assay development scientist, specialising in Immunology and allergy. Trained at St. George's Medical School and the University of Surrey, he is a Fellow of the Institute of Biomedical Science. He is currently the Scientific Director of Individual WellBeing Diagnostic Laboratories, where he has researched and developed a number of assays in the nutritional medicine field. He regularly lectures, on diagnostic tests to practitioners and colleges. He can be reached on Tel: 020-7730 7010.

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