Food, Agriculture & Environment
Abstract: Allergenicity of genetically modified food ( GM food ) has become a public concern and international expert panels e.g. WHO/ FAO have depicted decision trees for a rigorous assessment and testing for GM foods, especially where no history of safe use is available. The way to use patient sera for the assessment of allergenicity is still under discussion in cases of proteins where stability and protein sequences may not be conclusive or for potential new allergies. The risk assessment of immune hypersensitivity reactions induced potentially by GM food needs also to consider effects on other type of immune responses e.g. activation of specific immune cell populations. The role of antigen presenting cells of the gut is now understood to direct immune responses resulting in humoral, cellular or IgE predominant characteristics. For GM microorganisms potential effects on the immune system need to be assessed.
No specific international regulatory systems for GM foods safety or GMO environmental safety are currently in place. In the field of environmental safety the Cartagena Protocol on Biosafety may enter into force soon and Codex Alimentarius principles on human health risk analysis are expected to be adopted in 2003. The premise of these Codex principles dictates a premarket assessment, performed on a case-by-case basis and including an evaluation of both direct effects (from the inserted gene) and unintended effects (that may arise as a consequence of insertion of the new gene).
The safety assessment of GM foods investigates:
When new foods are developed by natural methods, some of the existing characteristics of foods can be altered unintentionally, either in a positive or a negative way. New plants developed through traditional breeding techniques may not be evaluated rigorously using risk assessment techniques2. In contrast to traditionally developed foods which are not generally tested for allergenicity before market introduction, protocols for testing detrimental immune responses, especially the allergenic potential of GM foods have been established by international expert panels2.
The Role of the Gut Immune System and Hypersensitivity Responses Food allergies and other food sensitivities are individualistic adverse reactions to foods because they affect only a few people in the population. Within the different types of reactions involved in adverse reactions to foods non-immunological intolerances (such as reactions to increased contents of histamins or intolerances against lactose) and reactions involving components of the immune system need to be differentiated3. In hypersensitivity reactions involving elements of the immune-system it became evident that these reactions are mainly caused by a lack of the induction of a tolerance against components of the foods in specific individuals. While research has delivered a very good understanding for the structural specificities of the protein food components which are often the cause for allergenic reactions, basic mechanisms underlying the reactions are at the focus of present research: Genetic and environmental factors are believed to influence antigen presenting cells, especially dendritic cells and T cell subsets which, using different sets of immune mediators, differentially regulate both, the synthesis of Immunoglobulin E which is the basis for humoral, immediate (or real, Type I) allergic hypersensitivity reactions and cellular reactions involving sensitized or self reactive T cells (delayed type, hypersensitivity reactions).
Antigen presenting cells belong to the gut associated lymphoid tissue (GALT). Immature dendritic cells reside in the epithelia also of the gut and have the potential to sense foreign antigens. Following recognition and uptake of Ag, mature dendritic cells provide signals which polarize Th0 cells into Th1 or Th2 cells, the basis for humoral or cellular immune-responses as well as decisions for the production of enhanced IgE4. Systemic immune responses to soluble oral antigens are most likely induced by gut-conditioned dendritic cells that function both to initiate the gut-oriented response and to impart the characteristic features that discriminate it from responses induced parenterally5. Also the differential stimulation of cytokines effecting immune responses and activation of the immune system was shown in intestinal epithelial immune cells using non-pathogenic E. coli and Lactobacilli6.
Specific microbes in the gut microflora and sporadic infections are so thought to be important in allergy prevention. The gastrointestinal microflora promotes potentially antiallergenic processes such as TH1-type immunity, suppression of TH2-induced allergic inflammation, induction of oral tolerance and IgA production. The gut microflora might therefore be a major postnatal counterregulator of the universal TH2-skewed immune system in fetuses and neonates7. Because of its role to serve as a barrier to pathogenic bacteria and to enable an immune surveillance of the antigenic environment the local mucosal immunity of the gut is of a central importance for health. Antigens, primarily associated with intestinal microbes and dietary antigens, can stimulate production of IgA in the intestine resulting in local protective immunity. Because of its role for a stimulation and regulation of immune responses the gut has become a favourite system for developments and techniques to interfere with modified or functional foods or vaccines including DNA vaccines 8,9,10.
GM Food and Hypersensitivity
These proteins mainly come from foods or food groups often referred to as “The Big Eight” which account for more than 90-percent of all Type I allergic reactions worldwide. These Big Eight are; milk, eggs, fish, crustacean shellfish, peanuts, soybeans, tree nuts and wheat 11. In response to pathogens, plants synthesize and accumulate a variety of proteins which are part of a plants defence system. As plant protection against bacteria, fungi, viruses and insects is a major challenge to agriculture world-wide, over-expression of such proteins in transgenic plants has been applied to increase the defense potential. Some of these proteins which are considered for use in the production of GMOs to increase the resistance to microbial and insectal attack include proteins with allergenic potential e.g. chitinases providing protection against fungal attack or insecticidal proteins including protease inhibitors12 .
Risk Assessment of Allergenicity
While the combination of these two criteria provides reasonable assurance that the introduced protein has limited allergenic potential, the ideal approaches to the application of these two criteria have been debated, and the desirability of adding other criteria for the allergenicity assessment of such products and additional testing has been advocated 14. The development of additional criteria and additional tests to use in the assessment of the allergenicity of GM foods would be advantageous in cases where the gene is obtained from sources with no history of allergenicity. The level of expression of the introduced protein and the functional category of the introduced protein could be used as additional criteria.
In addition, the development of suitable animal models for the prediction of the allergenic potential of the introduced proteins is anticipated in the future. While several animal models appear to be promising , none has been sufficiently validated for its routine use in the assessment of the allergenicity of GM foods. It must also be realised that the absence of sequence similarity with allergenic protein-epitopes and a missing stability against digestion does not necessarily prove for a missing allergenicity as examples are known which contradict to the general rules: Highly homologous sequences with allergens in case of allergen-isoforms have been shown without any allergenicity.
Furthermore, proteins with a low stability have been shown to exhibit a significant potency to induce allergenicity or to sensitize for allergic reactions17-19. The use of patients sera for the testing of allergenicity is therefore recommended20 .There is also some discussion if the generally agreed system is sensitive enough to detect upcoming new allergies in time. It is likely that the first manifestations of a new allergy will occur in pre-existing adult allergic individuals and could occur as a consequence of cross-reactivity. A screening programme may be desirable to predict such cross-reactivities by employing patients sera, however, the number of sera that would need to be screened may need to be much larger than that hitherto recommended in international documents 21.
Risk Assessment of Cell Mediated Reactions and Microbial Impact on the
Potential immune-stimulatory or immune-modulatory effects of GM microorganisms (GMMs) used as or in foods are a specific area of a risk assessment which evaluates immune responses to GM organisms. GMMs may establish themselves within the GI tract and exert influences on the immune system via interactions with the gut immune system. Even non-viable microorganisms are known to retain functional properties (i.e. cell adhesion, binding of chemicals, immunomodulating activities), which can have direct or indirect effects on both microflora- and host associated functions24. Gut-associated lymphoid tissue (GALT) has important interactions with the immune system and it is well established that microbial stimuli are the main antigenic forces in the development and maintenance of GALT and acquired immunity24. Stimulation of antigen presenting, dendritic cells influencing immune type responses was shown for bacterial cell walls before25 Potential safety relevant consequences from rare, but possible uptake of recombinant DNA from GM food by cells of the immune system remain to be investigated 26-28.
An improved investigation of activation pathways including antigen presenting- and T cells will not only contribute to a better understanding of these reactions but may also result in improved testing methods for allergenicity, where the possibilities for testing, especially of whole foods, in animal models are still limited.
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Last Updated on 5/14/03