Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Celiac Disease: a model autoimmune disease with gene therapy applications

Gene Therapy volume 10, pages 835–843 (2003)Cite this article

Abstract

Gene therapy (GT) is still at the ‘experimental’ stage and some recent setbacks have cooled the potential use of this therapeutic tool even in life-threatening conditions. However, this therapeutic approach has a potential, which is not limited to disease for which we have not other option. There are increasing evidence that GT will be soon used in diseases that are not life threatening. One group of diseases that can benefit from GT is the autoimmune one. Several experimental animal models have indicated the efficacy (proof of principle) of GT. In the present review, we have addressed the possibility that even extremely benign autoimmune-like diseases such as Celiac Disease (CD) might one day profit from this type of therapy. We further point that in conditions such as CD, where the trigger is well known and the pathogenic cascade is relatively well defined, a situation not common in autoimmunity, we can even have a better situation where to explore and use GT to control disease initiation and progression. Once the risks that are still intrinsic to GT will have been reduced the therapeutic options we outline in the present review might not appear too far from reality.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Somia N, Verma IM . Gene therapy: trials and tribulations. Nat Rev Genet 2000; 1: 91–99.

    Article  CAS  PubMed  Google Scholar 

  2. Verma IM, Somia N . Gene therapy – promises, problems and prospects. Nature 1997; 389: 239–242.

    Article  CAS  PubMed  Google Scholar 

  3. Griesenbach U, Ferrari S, Geddes DM, Alton EW . Gene therapy progress and prospects: cystic fibrosis. Gene Ther 2002; 9: 1344–1350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fischer A, Hacein-Bey S, Cavazzana-Calvo M . Gene therapy of severe combined immunodeficiencies. Nat Rev Immunol 2002; 2: 615–621.

    Article  CAS  PubMed  Google Scholar 

  5. Kessels HW, Wolkers MC, van dB, van der Valk MA, Schumacher TN . Immunotherapy through TCR gene transfer. Nat Immunol 2001; 2: 957–961.

    Article  CAS  PubMed  Google Scholar 

  6. Thomas ED . The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine, 1990. Bone marrow transplantation – past, present and future. Scand J Immunol 1994; 39: 339–345.

    Article  CAS  PubMed  Google Scholar 

  7. Viganego F, Nash R, Furst DE . Bone marrow transplantation in the treatment of systemic sclerosis. Curr Rheumatol Rep 2000; 2: 492–500.

    Article  CAS  PubMed  Google Scholar 

  8. Mandalfino P et al. Bone marrow transplantation in multiple sclerosis. J Neurol 2000; 247: 691–695.

    Article  CAS  PubMed  Google Scholar 

  9. Brodsky RA, Smith BD . Bone marrow transplantation for autoimmune diseases. Curr Opin Oncol 1999; 11: 83–86.

    Article  CAS  PubMed  Google Scholar 

  10. Chernajovsky Y, Adams G, Triantaphyllopoulos K, Ledda MF, Podhajcer OL . Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model. Gene Ther 1997; 4: 553–559.

    Article  CAS  PubMed  Google Scholar 

  11. Nakajima A et al. Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. J Clin Invest 2001; 107: 1293–1301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaw MK et al. Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med 1997; 185: 1711–1714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morita Y et al. Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis. J Clin Invest 2001; 107: 1275–1284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang HG et al. Induction of specific T cell tolerance by Fas ligand-expressing antigen-presenting cells. J Immunol 1999; 162: 1423–1430.

    CAS  PubMed  Google Scholar 

  15. Tomita T et al. Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy. Arthritis Rheum 1999; 42: 2532–2542.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang HG et al. Gene therapy that inhibits nuclear translocation of nuclear factor kappaB results in tumor necrosis factor alpha-induced apoptosis of human synovial fibroblasts. Arthritis Rheum 2000; 43: 1094–1105.

    Article  CAS  PubMed  Google Scholar 

  17. Maki M, Collin P . Coeliac disease. Lancet 1997; 349: 1755–1759.

    Article  CAS  PubMed  Google Scholar 

  18. Fasano A, Catassi C . Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001; 120: 636–651.

    Article  CAS  PubMed  Google Scholar 

  19. Loftus CG, Loftus Jr EV . Cancer risk in celiac disease. Gastroenterology 2002; 123: 1726–1729.

    Article  PubMed  Google Scholar 

  20. Sollid LM . Molecular basis of celiac disease. Annu Rev Immunol 2000; 18: 53–81.

    Article  CAS  PubMed  Google Scholar 

  21. Maiuri L et al. Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology 1996; 110: 1368–1378.

    Article  CAS  PubMed  Google Scholar 

  22. Maiuri L et al. Blockage of T-cell costimulation inhibits T-cell action in celiac disease. Gastroenterology 1998; 115: 564–572.

    Article  CAS  PubMed  Google Scholar 

  23. Korponay-Szabo IR et al. Missing endomysial and reticulin binding of coeliac antibodies in transglutaminase 2 knockout tissues. Gut 2003; 52: 199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Maki M, Hallstrom O, Marttinen A . Reaction of human non-collagenous polypeptides with coeliac disease autoantibodies. Lancet 1991; 338: 724–725.

    Article  CAS  PubMed  Google Scholar 

  25. Maki M, Huupponen T, Holm K, Hallstrom O . Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut 1995; 36: 239–242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Amara W, Husebekk A . Improved method for serological testing in celiac disease – IgA anti-endomysium antibody test: a comparison between monkey oesophagus and human umbilical cord as substrate in indirect immunofluorescence test. Scand J Clin Lab Invest 1998; 58: 547–554.

    Article  CAS  PubMed  Google Scholar 

  27. Dieterich W et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997; 3: 797–801.

    Article  CAS  PubMed  Google Scholar 

  28. Dieterich W et al. Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology 1998; 115: 1317–1321.

    Article  CAS  PubMed  Google Scholar 

  29. Sulkanen S et al. Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology 1998; 115: 1322–1328.

    Article  CAS  PubMed  Google Scholar 

  30. Molberg O et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998; 4: 713–717.

    Article  CAS  PubMed  Google Scholar 

  31. van de WY et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998; 161: 1585–1588.

    Google Scholar 

  32. Quaratino S, Feldmann M, Dayan CM, Acuto O, Londei M . Human self-reactive T cell clones expressing identical T cell receptor beta chains differ in their ability to recognize a cryptic self-epitope. J Exp Med 1996; 183: 349–358.

    Article  CAS  PubMed  Google Scholar 

  33. Michaelsson E et al. T cell recognition of carbohydrates on type II collagen. J Exp Med 1994; 180: 745–749.

    Article  CAS  PubMed  Google Scholar 

  34. Manoury B et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol 2002; 3: 169–174.

    Article  CAS  PubMed  Google Scholar 

  35. Anderton SM, Viner NJ, Matharu P, Lowrey PA, Wraith DC . Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nat Immunol (2002).

  36. Shan L et al. Structural basis for gluten intolerance in celiac sprue. Science 2002; 297: 2275–2279.

    Article  CAS  PubMed  Google Scholar 

  37. Arentz-Hansen H et al. The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 2000; 191: 603–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kutlu T et al. Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut 1993; 34: 208–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jabri B et al. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology 2000; 118: 867–879.

    Article  CAS  PubMed  Google Scholar 

  40. Maiuri L et al. IL-15 drives the specific migration of CD94+ and TCR-gamma delta+ intraepithelial lymphocytes in organ cultures of treated celiac patients. Am J Gastroenterol 2001; 96: 150–156.

    CAS  PubMed  Google Scholar 

  41. Maiuri L et al. FAS engagement drives apoptosis of enterocytes of coeliac patients. Gut 2001; 48: 418–424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ciccocioppo R et al. Mechanisms of villous atrophy in autoimmune enteropathy and coeliac disease. Clin Exp Immunol 2002; 128: 88–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bauer S et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285: 727–729.

    Article  CAS  PubMed  Google Scholar 

  44. Maiuri L et al. Interleukin 15 mediates epithelial changes in celiac disease. Gastroenterology 2000; 119: 996–1006.

    Article  CAS  PubMed  Google Scholar 

  45. Forsberg G et al. Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease. Gastroenterology 2002; 123: 667–678.

    Article  CAS  PubMed  Google Scholar 

  46. Przemioslo RT et al. Histological changes in small bowel mucosa induced by gliadin sensitive T lymphocytes can be blocked by anti-interferon gamma antibody. Gut 1995; 36: 874–879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nilsen EM et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 1998; 115: 551–563.

    Article  CAS  PubMed  Google Scholar 

  48. Fehniger TA, Caligiuri MA . Interleukin 15: biology and relevance to human disease. Blood 2001; 97: 14–32.

    Article  CAS  PubMed  Google Scholar 

  49. Bu P et al. Apoptosis: one of the mechanisms that maintains unresponsiveness of the intestinal mucosal immune system. J Immunol 2001; 166: 6399–6403.

    Article  CAS  PubMed  Google Scholar 

  50. Waldmann TA, Dubois S, Tagaya Y . Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 2001; 14: 105–110.

    CAS  PubMed  Google Scholar 

  51. Ruchatz H et al. Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol 1998; 160: 5654–5660.

    CAS  PubMed  Google Scholar 

  52. Cellier C et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 2000; 356: 203–208.

    Article  CAS  PubMed  Google Scholar 

  53. Corrao G et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001; 358: 356–361.

    Article  CAS  PubMed  Google Scholar 

  54. Rabinovich GA et al. Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J Exp Med 1999; 190: 385–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Annenkov A, Chernajovsky Y . Engineering mouse T lymphocytes specific to type II collagen by transduction with a chimeric receptor consisting of a single chain Fv and TCR zeta. Gene Ther 2000; 7: 714–722.

    Article  CAS  PubMed  Google Scholar 

  56. Berlin C et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74: 185.

    Article  CAS  PubMed  Google Scholar 

  57. Briskin M et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997; 151: 97–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Barbara G et al. Interleukin 10 gene transfer prevents experimental colitis in rats. Gut 2000; 46: 344–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wirtz S, Galle PR, Neurath MF . Efficient gene delivery to the inflamed colon by local administration of recombinant adenoviruses with normal or modified fibre structure. Gut 1999; 44: 800–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Steidler L et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000; 289: 1352–1355.

    Article  CAS  PubMed  Google Scholar 

  61. Van Montfrans C et al. Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model. Gastroenterology 2002; 123: 1865–1876.

    Article  CAS  PubMed  Google Scholar 

  62. Pollok KE et al. Costimulation of transduced T lymphocytes via T cell receptor-CD3 complex and CD28 leads to increased transcription of integrated retrovirus. Hum Gene Ther 1999; 10: 2221–2236.

    Article  CAS  PubMed  Google Scholar 

  63. Van Montfrans C et al. Generation of regulatory gut-homing human T lymphocytes using ex vivo interleukin 10 gene transfer. Gastroenterology 2002; 123: 1877–1888.

    Article  CAS  PubMed  Google Scholar 

  64. Halene S et al. Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector. Blood 1999; 94: 3349–3357.

    CAS  PubMed  Google Scholar 

  65. Blaese RM et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 1995; 270: 475–480.

    Article  CAS  PubMed  Google Scholar 

  66. Bonini C et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  PubMed  Google Scholar 

  67. Halttunen T, Maki M . Serum immunoglobulin A from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation. Gastroenterology 1999; 116: 566–572.

    Article  CAS  PubMed  Google Scholar 

  68. Dubois S et al. Natural splicing of exon 2 of human interleukin-15 receptor alpha-chain mRNA results in a shortened form with a distinct pattern of expression. J Biol Chem 1999; 274: 26978–26984.

    Article  CAS  PubMed  Google Scholar 

  69. Wei X et al. The Sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. J Immunol 2001; 167: 277–282.

    Article  CAS  Google Scholar 

  70. Dubois S, Mariner J, Waldmann TA, Tagaya Y . IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity 2002; 17: 537–547.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The present study has been supported by European Community Grant QLK1-CT-1999-00037 and Arthritis Research Campaign, UK.

Author information

Authors and Affiliations

  1. Institute of Child Health, University College London, London, UK

    M Londei & L Maiuri

  2. Cancer Sciences Division, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK

    S Quaratino

  3. Department of Pediatrics, University Federico II, Naples, Italy

    L Maiuri

Authors
  1. M Londei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Quaratino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Maiuri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Londei.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Londei, M., Quaratino, S. & Maiuri, L. Celiac Disease: a model autoimmune disease with gene therapy applications. Gene Ther 10, 835–843 (2003). https://doi.org/10.1038/sj.gt.3302041

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302041

This article is cited by

Search

Advanced search

Quick links