Therapeutic Vaccines for Allergy in GM Rice

Known to cause asthma in clinical trials. Prof. Joe Cummins

The immune system has learned to distinguish between self and non-self. The cells lining the digestive system or airways encounter antigens in food and numerous non-pathogenic bacteria. To cope with food or bacteria that are not harmful, the immune system develops oral tolerance. Repeated exposure to antigens in food or harmless bacteria leads to a state of oral tolerance in which the antigen is recognized as self and does not provoke an immune response [1].

Allergic and autoimmune diseases are forms of immune hypersensitivity  that increasingly cause ill health. Most current therapies for the diseases treat symptoms rather then the underlying causes. The pathologically hypersensitive can be desensitized using vaccines consisting of synthetic peptides representing ‘T cell epitopes’, the portion of the antigens provoking the immune response [2]. T cells are the key mediators of specific immune responses against infectious diseases or cancer, and are also involved in allergies. A crucial event in T cell activation is the presentation of peptides derived from protein antigens. This event is accomplished by the intracellular fragmentation of specific protein antigens, followed by the binding of the resultant peptide epitopes to HLA  (Human Leukocyte Antigen) molecules and presented on the cell surface of antigen presenting cells (APCs) for recognition by specific T-cell receptors.

Synthetic T-cell epitopes derived from the primary sequence of allergen molecules are used to down regulate allergic inflammation in sensitized individuals in a manner similar to oral tolerance. The approach has a substantial advantage over treatment with entire allergen molecules, which often persist in activating the cells involved in allergic inflammation [3]. The therapeutic peptide epitopes are ingested, delivered through airways or injected into the bloodstream. Clinical trials of T cell epitope peptides using injection proved equivocal; a number of studies found that the peptides actually induced an asthmatic response [4].

 GM rice was developed to treat allergy. This development may lead to an avalanche of GM pharm crops to fight allergies such as cat, dust mites, nuts, etc. The T cell epitopes for the Japanese cedar pollen allergy peptide are used to create oral tolerance (oral intake of allergens to create tolerance by causing the immune system to regard the allergen as food and thus safe). The epitope peptides are selected, cutting out the parts of the original protein triggering the allergy response, sneezing, coughing , etc). Inducing oral tolerance relieves the allergic response to cedar pollen. Introducing the T- cell epitopes into rice is achieved by introducing the gene segment specifying the epitope  causing the allergy in humans fused to the soybean seed storage protein glycinin into the rice genome so that a rice meal should prevent the allergic response to cedar pollen. The  epitope gene was driven by a rice glutelin promoter, followed  by a glutelin signal peptide sequence, a rice endoplasmic retention signal and a transcription termination gene from rice glutelin. The gene insert cassette also included a hygromycin  antibiotic resistance gene driven by a CaMV promoter and transcription was  terminated by a agropine sequence [5, 6]. Sneezing transgenic mice exposed to the allergen were relieved of allergy symptoms and the accompanying serum allergen  IgE and IgG antibodies and CD4+ proliferation response [6].

The use of rice to treat allergy has the potential to pollute the rice food crop with genes causing allergy in humans and an antibiotic resistance gene. The report also did not consider detrimental side-effects of the epitope peptides, for example the asthma reported in humans during clinical trials.  However, there is little doubt that the use of human T cell epitope peptides produced in crop plants to treat a wide array of allergies and autoimmune diseases is going to be a major focus in the very near future. These developments may well exacerbate the current “major epidemic” of asthma if unchecked.

Please send this paper to your policy-makers and demand strict regulation, risk assessment and safety studies on these crops.

Article first published 31/03/06

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References

1. Mayer L. and Shao L.  Therapeutic potential of oral tolerance. Nature Rev. Immunol. 2004, 4, 407-19.
2. Larche M. and Wraith D. Peptide-based therapeutic vaccines for allergenic and autoimmune diseases.  Nature Medicine supplement 2005, 11, S69-S76.
3. Verhoef A, Alexander C, Kay A. and Larche M. T cell immunotherapy induces a CD4 T cell population with regulatory activity. PLOS Medicine 2005, 2, 0253-0261.
4. Linhart B. and Valenta R. Molecular design of allergy vaccines. 2005, current opinion in immunology 17,1-10.
5. Takagi H, Saito S, Yang L, Nagasaka S, Nishizawa N and Takaiwa F. Oral immunotherapy against a pollen allergy using a seed based peptide vaccine. Plant Biotechnology Journal 2005, 3, 521-33.
6.  Takagi H, Hiroi T, Yang L, Tada Y, Yuki Y, Takamura K, Ishimitsu R, Kawauchi H, Kiyono H, and Takaiwa F. 2005 A rice-based edible vaccine expressing multiple T cell epitopes induces oral tolerance for inhibition of Th2-mediated IgE responses.. Proc. Natl Acad. Sci. USA. 2005 doi/10.1073/pnas.0503428102 (early edition Nov. 8)