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86 IMMUNOTHERAPY OF COELIAC DISEASE hypothetical use of IL10 in the treatment of intestinal disorders, there are many evidences both in vitro, in the fetal organ culture system, and in vivo, in a mouse model of inflammatory colitis, that IL10 or cells producing it, such as Tr1 cells, are able to downregulate T cell activation and to control the pathogenic process. Moreover several reports showed that IL10 may have a central role in the development and homeostasis of gut associated immune system (GALT). We know that in the mucosa of untreated coeliac patients IL10 mRNA levels (and protein level) are higher than in controls, but they face, and cannot efficiently contrast, enormously higher levels of proinflammatory 6 cytokines as gamma interferon . Also the addition of further exogenous IL10 to the organ culture of biopsies from untreated coeliac patients fail to control the inflammatory process (Salvati et al, unpublished observations). Nonetheless, the addition of IL10 in the organ culture system of treated coeliac mucosa challenged with gliadin is able to downregulate the specific mucosal immune response to gliadin in terms of reduced densities of CD25+ cells, reduced expression of CD80/CD86 21 costimulatory molecules and of mRNA for inflammatory cytokines . Moreover, preliminary evidences show that the production of g-interferon upon gliadin stimulation is still absent 3 weeks later the isolation of T cells from biopsies cultured with gliadin in presence of IL10. Interestingly, the effect is partially reverted by the addition of anti-IL10 receptor and of anti-TGF b, this further suggesting the presence of an active suppressive mechanism, maybe mediated by regulatory T cells. In conclusion, our results showed that immunomodulation by IL10 on gliadin reactive T cells could be a consequence of downregulation of costimulatory molecules but also suggest that IL10 may operate through induction of Tr1 cells and inhibits the migration into the intestine of pathogenic Th1 cells. Given that, the induction or the expansion of specific T regulatory cells remains one of the possible immunomodulatory strategies to implement in CD. Mucosal tolerance A very efficient route to induce tolerance to a specific antigen is the intravenous administration, but the induction of tolerance via mucosae is a strategy more often implemented in the experimental therapy of autoimmune diseases. Nevertheless, in CD, being the small intestine the target of the disease, mucosae other than those of the small intestine are candidate to elicit mucosal tolerance. Despite its peculiar physicochemical properties, gliadin has been shown to be a good oral tolerogen. We studied the potential for tolerance induction in gluten-free diet Balb/c mice by intranasal administration of whole antigen, as it has been demonstrated that this 22 strategy is effective in a variety of different experimental systems . Our results showed that intranasal administration of native gliadin before immunization abrogated the specific T cell response. Moreover, a marked decrease in g-interferon and IL-2 levels, and normal levels of IL-4 expression were detected, suggesting that intranasal 23 administration of gliadin can induce tolerance in Th1-cells . These data were produced in mice parenterally immunized with gliadin: it is a model quite far from CD, but yet it offers a series of questions, in particular concerning the ability of the nasal administration of antigen to tolerate also gut T responses and to control a Th1 mediated enteropathy.
IMMUNOTHERAPY OF COELIAC DISEASE 87 In conclusion, CD has a strong T component that renders it susceptible of immunomodulation. There are still a number of significant theoretical problems to be solved, first of all the relevance of the non-T pathogenetic component. In any case the strategy eventually chosen must be really "competitive" with the safety of the glutenfree diet. Acknowledgements Most of the studies reported in this paper have been carried out with financial support from the commission of the European Communities, specific RTD programme "Quality of Life and Management of Living Resources", QLK1-CT-1999-00037, Evaluation of the prevalence of coeliac disease and its genetic components in the European population. References 1. Auricchio S, Troncone R, Maurano F. Coeliac disease in the year 2000. Ital J Gastroenterol Hepatol 1999; 31: 773-80. 2. Kagnoff, MF. HLA genes in Coeliac Disease. In: Auricchio S, Greco L, Maiuri L, Troncone R, eds. Coeliac disease. Naples: Jean Gilder Editions, 2000; 5-14. 3. Sollid LM. Molecular basis of coeliac disease. Ann Rev Immunol 2000; 18: 53- 81. 4. Maiuri L, Picarelli A, Boirivant M, Coletta S, Mazzilli MC, De Vincenzi M, et al. Definition of the initial immunologic modification upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology 1996; 110: 1368-78. 5. Maiuri L, Ciacci C, Raia V, Vacca L, Ricciardelli I, Raimondi F, et al. FAS engagement drives apoptosis of enterocytes of coeliac patients.Gut 2001; 48: 418-24. 6. Salvati VM, Troncone R, Mazzarella G, et al. High levels of IFN-gmRNA in untreated celaics and in treated mucosa in vitro cultured with gliadin. Ital J Gastroenterol Hepatol 1999; 31: 559. 7. Bluestone JA. New perspective of CD28/B7-mediated T cell costimulation. Immunity 1995; 2: 555. 8. Levisetti MG, Padrid PA, Szot GL, Mittal N, Meehan SM, Wardrip CL, et al. Immunosuppressive effect of human CTLA4Ig in a nonhuman primate model of allogeneic pancreatic islet transplantation. J Immunol 1997; 159: 5187. 9. Lenshow DY, Zeng J, Thistlethwaite JR, Montag A, Brady W, Gibson M, et al. Long term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 1992; 257: 789. 10. Maiuri L, Auricchio S, Coletta S, De Marco G, Picarelli S, Di Tola M, et al. Blockage of T cell costimulation inhibits T-cell action in celiac disease. Gastroenterology 1998; 115: 564-72. 11. Whindhagen A, Scholz C, Hollsberg P, Fukaura H, Sette A, DA Hafler. Modulation of cytokine patterns of human autoreactive T cell clones by a single aminoacid substitution of their peptide ligand. Immunity 1995; 2: 373. 12. De Magistris MT, Alexander J, Coggeshall M, Altman A, Gaeta F, Grey HM, et
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Perspectives on Coeliac Disease Vol
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The AIC Meeting was held in the Aul
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Italian Coeliac Society, Via Picott
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Preface Coeliac disease (CD) is a u
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Contents Current understanding of t
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2 THE BASIS OF COELIAC DISEASE hapl
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4 THE BASIS OF COELIAC DISEASE 1 pr
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6 THE BASIS OF COELIAC DISEASE spre
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8 THE BASIS OF COELIAC DISEASE Ackn
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10 THE BASIS OF COELIAC DISEASE glu
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Catassi C, Fasano A, Corazza GR (ed
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T CELL RESPONSES TO GLUTEN PEPTIDES
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18 A DOMINANT EPITOPE IN GLUTEN PEP
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28 ROLE OF A-GLIADIN 31-49 PEPTIDE
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Catassi C, Fasano A, Corazza GR (ed
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COELIAC DISEASE IN THE SAHARAWI 33
Page 49 and 50: COELIAC DISEASE IN THE SAHARAWI 35
Page 55: COELIAC DISEASE IN THE SAHARAWI 41
Page 58 and 59: 44 INFANT FEEDING PRACTICES AND COE
Page 66 and 67: Age (years) 52 INFANT FEEDING PRACT
Page 76 and 77: 62 MECHANISMS OF ORAL TOLERANCE the
Page 78 and 79: 64 MECHANISMS OF ORAL TOLERANCE pot
Page 80 and 81: 66 MECHANISMS OF ORAL TOLERANCE Epi
Page 82 and 83: 68 MECHANISMS OF ORAL TOLERANCE typ
Page 84 and 85: 70 MECHANISMS OF ORAL TOLERANCE 51
Page 86 and 87: 72 MECHANISMS OF ORAL TOLERANCE 23.
Page 89 and 90: Catassi C, Fasano A, Corazza GR (ed
Page 91 and 92: GENETICALLY DETOXIFIED GRAINS 77 to
Page 93 and 94: • • GENETICALLY DETOXIFIED GRAI
Page 95 and 96: GENETICALLY DETOXIFIED GRAINS 81 3.
Page 99: IMMUNOTHERAPY OF COELIAC DISEASE 85
Page 105 and 106: RECENT ADVANCES ON GLUTEN TOXICITY
Page 107 and 108: Index A Antiendomysium antibodies (
Page 109: INDEX 95 W Wheat, 7, 23, 27, 31, 53
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