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* Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;
Department of Immunology, Mayo Clinic, Rochester, MN;
Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN;
Department of Hematoimmunology, Leids Universitair Medisch Centrum, Leiden, the Netherlands;
¶ Department for Molecular Biomedical Research, Vlaams Interuniversitair Instituut voor Biotechnologie, Ghent, Belgium;
|| ActoGeniX NV, Zwijnaarde, Belgium;
# Department of Gastroenterology and Hepatology, Leids Universitair Medisch Centrum, Leiden, the Netherlands
Active delivery of recombinant autoantigens or allergens at the intestinal mucosa by genetically modified Lactococcus lactis (LL) provides a novel therapeutic approach for the induction of tolerance. Celiac disease is associated with either HLA-DQ2- or HLA-DQ8-restricted responses to specific antigenic epitopes of gliadin, and may be treated by induction of Ag-specific tolerance. We investigated whether oral administration of LL-delivered DQ8-specific gliadin epitope induces Ag-specific tolerance. LL was engineered to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and the induction of Ag-specific tolerance was studied in NOD AB° DQ8 transgenic mice. Tolerance was assessed by delayed-type hypersensitivity reaction, cytokine measurements, eDQ8d-specific proliferation, and regulatory T cell analysis. Oral administration of LL-eDQ8d induced suppression of local and systemic DQ8-restricted T cell responses in NOD AB° DQ8 transgenic mice. Treatment resulted in an Ag-specific decrease of the proliferative capacity of inguinal lymph node (ILN) cells and lamina propria cells. Production of IL-10 and TGF-β and a significant induction of Foxp3+ regulatory T cells were associated with the eDQ8d-specific suppression induced by LL-eDQ8d. These data provide support for the development of effective therapeutic approaches for gluten-sensitive disorders using orally administered Ag-secreting LL. Such treatments may be effective even in the setting of established hypersensitivity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The trademarks TopAct and ActoBiotics are used with the permission of ActoGeniX. This study was supported by National Institutes of Health Grant DK071003.
2 Address correspondence and reprint requests to Dr. Joseph A. Murray, Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail address: Murray.joseph{at}mayo.edu
3 Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; DTH, delayed type hypersensitivity; DQ8d, deamidated DQ8-specific gliadin epitope; eDQ8d, deamidated DQ8-specific gliadin epitope that is immunodominant for DQ8-mediated T cell responses; GALT, gut-associated lymphoid tissue; ILN, inguinal lymph node; LAP, latency-associated peptide; LL, Lactococcus lactis; LL-pT1NX, LL MG1363 containing empty vector; LL-eDQ8d, LL-secreting eDQ8d; MFI, mean fluorescence intensity; nTregs, naturally occurring Tregs.
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