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Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance

Abstract

Oral administration of protein can induce antigen-specific immune hyporesponsiveness1. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plants may be ideally suited for this purpose, as they can synthesize, glycosylate and assemble mammalian proteins to provide huge quantities of relatively low cost soluble proteins2. Furthermore, edible transgenic plants could provide a simple and direct method of autoantigen delivery for oral tolerance. Therefore, the aim of this study was to determine whether a transgenic plant expression system was capable of synthesizing the diabetes-associated autoantigen, glutamic acid decar-boxylase (GAD)3,4 in an immunogenic form and whether the oral administration of an autoantigen expressed by a plant could directly induce protective immune responses in a mouse model of diabetes. We show that a GAD-expressing transgenic plant, given as a dietary supplement, inhibits the development of diabetes in the non-obese diabetic (NOD) mouse.

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References

  1. Weiner, H.L. et al. Oral tolerance: Immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu. Rev. Immunol. 12, 809–837 (1994).

    Article  CAS  Google Scholar 

  2. Sijmons, P.C. et al. Production of correctly processed human serum albumin in transgenic plants. BioTechnology 8, 217–221 (1990).

    CAS  PubMed  Google Scholar 

  3. Tisch, R. et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366, 72–75 (1993).

    Article  CAS  Google Scholar 

  4. Kaufman, D.L. et al. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366, 69–72 (1993).

    Article  CAS  Google Scholar 

  5. De Aizpura, H.J., Wilson, Y.M. & Harrison, L.C. Glutamic acid decarboxylase autoantibodies in preclinical insulin-dependent diabetes. Proc. Natl. Acad. Sci. USA 89, 9841–9845 (1992).

    Article  Google Scholar 

  6. Makino, S. et al. Breeding of non-obese diabetic strain of mice. Exp. Anim. 29, 1–13 (1980).

    Article  CAS  Google Scholar 

  7. Elliott, J.F. et al. Immunization with the larger isoform of mouse glutamic acid decarboxylase (GAD67) prevents autoimmune diabetes in NOD mice. Diabetes 43, 1494–1499 (1994).

    Article  CAS  Google Scholar 

  8. Tian, J. et al. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 183, 1561–1567 (1996).

    Article  CAS  Google Scholar 

  9. Tian, J. et al. Modulating autoimmune response to GAD inhibits disease progression and prolongs graft survival in diabetes-prone mice. Nature Med. 2, 1348–1353 (1996).

    Article  CAS  Google Scholar 

  10. Kaufman, D.L., McGinnis, J.F., Krieger, N.R. & Tobin, A.J. Brain glutamate decarboxylase cloned in lambda gt-11: Fusion protein produces gamma-aminobutyric acid. Science 232, 1138–1140 (1986).

    Article  CAS  Google Scholar 

  11. Katarova, Z., Szabo, G., Mugnaini, E. & Greenspan, R.J. Molecular characterization of the 62 kD form of glutamic acid decarbonxylase from the mouse. Eur. J. Neurosci. 2, 190–202 (1990).

    Article  Google Scholar 

  12. Karlsen, A.E. et al. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase form chromosome 10. Proc. Natl. Acad. Sci. USA 88, 8337–8341 (1991).

    Article  CAS  Google Scholar 

  13. Friedman, A. & Weiner, H.L. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc. Natl. Acad. Sci. USA 91, 6688–6692 (1994).

    Article  CAS  Google Scholar 

  14. Chen, Y. et al. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 376, 177–180 (1995).

    Article  CAS  Google Scholar 

  15. Zhang, Z.J., Davidson, L., Eisenbarth, G. & Weiner, H.L. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc. Natl. Acad. Sci. USA 88, 10252–10256 (1991).

    Article  CAS  Google Scholar 

  16. Qin, H.-Y. et al. GAD specific T cell tolerance and TH1 to TH2 switch in mouse GAD67 or adjuvant immunized NOD mice. Autoimmunity 21, 50 (1995).

    Google Scholar 

  17. Haq, T.A., Mason, H.S., Clements, J.D. & Arntzen, C.J. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science 268, 714–716 (1995).

    Article  CAS  Google Scholar 

  18. Genain, C.P. et al. Late complications of immune deviation therapy in a non-human primate. Science 274, 2054–2057 (1996).

    Google Scholar 

  19. Blanas, E., Carbone, F.R., Allison, J., Miller, J.F.A.P. & Health, W.R. Induction of autoimmune diabetes by oral administration of autoantigen. Science 274, 1707–1709 (1990).

    Article  Google Scholar 

  20. Carrington, J.C. & Freed, D.D. Cap-independent enhancement of translation by a plant potyvirus 5′ nontranslated region. J. Virol. 64, 1590–1597 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ditta, G., Stanfield, S., Corbin, D. & Helinski, D.R. Broad host range DNA cloning system for gram-negative bacteria: construction of a gene bank of Rhizobium meliloti. Proc. Natl. Acad. Sci. USA 77, 7347–7351 (1980).

    Article  CAS  Google Scholar 

  22. Horsch, R.B. et al. A simple and general method for transferring genes into plants. Science 227, 1229–1231 (1985).

    Article  CAS  Google Scholar 

  23. De Block, M. Genotype-independent leaf disc transformation of potato (Solanum tuberosum) using Agrobacterium Tumefaciens. Theor. Appl. Genet. 76, 767–774 (1988).

    Article  CAS  Google Scholar 

  24. Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).

    Article  CAS  Google Scholar 

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Ma, SW., Zhao, DL., Yin, ZQ. et al. Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance. Nat Med 3, 793–796 (1997). https://doi.org/10.1038/nm0797-793

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