Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin

Gastroenterology. 2007 Aug;133(2):517-28. doi: 10.1053/j.gastro.2007.04.073. Epub 2007 May 3.

Abstract

Background and aims: Obtaining antigen-specific immune suppression is an important goal in developing treatments of autoimmune, inflammatory, and allergic gastrointestinal diseases. Oral tolerance is a powerful means for inducing tolerance to a particular antigen, but implementing this strategy in humans has been difficult. Active delivery of recombinant autoantigens or allergens at the intestinal mucosa by genetically modified Lactococcus lactis (L lactis) provides a novel therapeutic approach for inducing tolerance.

Methods: We engineered the food grade bacterium L lactis to secrete ovalbumin (OVA) and evaluated its ability to induce OVA-specific tolerance in OVA T-cell receptor (TCR) transgenic mice (DO11.10). Tolerance induction was assessed by analysis of delayed-type hypersensitivity responses, measurement of cytokines and OVA-specific proliferation, phenotypic analysis, and adoptive transfer experiments.

Results: Intragastric administration of OVA-secreting L lactis led to active delivery of OVA at the mucosa and suppression of local and systemic OVA-specific T-cell responses in DO11.10 mice. This suppression was mediated by induction of CD4(+)CD25(-) regulatory T cells that function through a transforming growth factor beta-dependent mechanism. Restimulation of splenocytes and gut-associated lymph node tissue from these mice resulted in a significant OVA-specific decrease in interferon gamma and a significant increase in interleukin-10 production. Furthermore, Foxp3 and CTLA-4 were significantly up-regulated in the CD4(+)CD25(-) population.

Conclusions: Mucosal antigen delivery by oral administration of genetically engineered L lactis leads to antigen-specific tolerance. This approach can be used to develop effective therapeutics for systemic and intestinal immune-mediated inflammatory diseases.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adoptive Transfer
  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigens, CD / metabolism
  • Antigens, Differentiation / metabolism
  • CTLA-4 Antigen
  • Cell Proliferation
  • Dose-Response Relationship, Immunologic
  • Female
  • Forkhead Transcription Factors / metabolism
  • Hypersensitivity, Delayed / immunology*
  • Hypersensitivity, Delayed / metabolism
  • Immune Tolerance*
  • Immunity, Mucosal
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-2 Receptor alpha Subunit / analysis
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Intestines / immunology*
  • Lactococcus lactis / genetics
  • Lactococcus lactis / metabolism*
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Ovalbumin / biosynthesis
  • Ovalbumin / genetics
  • Ovalbumin / immunology*
  • Peyer's Patches / cytology
  • Peyer's Patches / immunology
  • Peyer's Patches / metabolism
  • Probiotics / administration & dosage
  • Probiotics / metabolism*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Recombinant Proteins / immunology
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / transplantation
  • Transforming Growth Factor beta / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interferon-gamma
  • Ovalbumin