title: Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice.
abstract: 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 degrees 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 degrees 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-beta 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.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Inge L
authors.initials: IL
authors.lastname: Huibregtse
authors.forename: Eric V
authors.initials: EV
authors.lastname: Marietta
authors.forename: Shadi
authors.initials: S
authors.lastname: Rashtak
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
authors.forename: Pieter
authors.initials: P
authors.lastname: Rottiers
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Sander J H
authors.initials: SJ
authors.lastname: van Deventer
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002446:Celiac Disease / Q000276:immunology / Q000382:microbiology / Q000628:therapy; D002999:Clone Cells; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D005903:Gliadin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007114:Immunization; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013294:Lactococcus lactis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D005903:Gliadin