Induction of Ovalbumin-Specific Tolerance by Oral Administration of Lactococcus lactis Secreting Ovalbumin

Background & 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 β-dependent mechanism. Restimulation of splenocytes and gut-associated lymph node tissue from these mice resulted in a significant OVA-specific decrease in interferon γ 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.

Abbreviations used in this paper: APC, antigen presenting cell, BM, bone marrow, DC, dendritic cells, DTH, delayed type hypersensitivity, GALT, gut-associated lymphoid tissue, IFN, interferon, IL, interleukin, LL, Lactococcus lactis, LL-OVA, OVA-secreting L lactis, OT, oral tolerance, OVA, ovalbumin, TCR, T-cell receptor, Treg, regulatory T cell