Abstract
Genetically modified Lactococcus lactis bacteria have been engineered as a tool to deliver bioactive proteins to mucosal tissues as a means to exert both local and systemic effects. They have an excellent safety profile, the result of years of human consumption in the food industry, as well as a lack of toxicity and immunogenicity. Also, containment strategies have been developed to promote further application as clinical protein-based therapeutics. Here, we review technological advancements made to enhanced the potential of L. lactis as live biofactories and discuss some examples of tolerogenic immunotherapies mediated by mucosal drug delivery via L. lactis. Additionally, we highlight their use to induce mucosal tolerance by targeted autoantigen delivery to the intestine as an approach to reverse autoimmune type 1 diabetes.
Highlights
The mucosal immune system in close interaction with symbiotic bacteria is constantly working to maintain a homeostatic balance between immune activation, which is necessary against vast amounts of exogenous antigens and noxious stimuli, and immune tolerance toward harmless inhaled or ingested antigens and the host microbiota
A phase-II trial that evaluated the efficacy of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis (OM) showed the spray was safe, well tolerated, and effective in reducing the frequency and severity of OM in patients with colorectal cancer treated with chemotherapy [75]
Delivery of a deamidated gliadin epitope, an immunodominant epitope in celiac disease, by L. lactis to transgenic humanized non-obese diabetic (NOD) AB°DQ8 mice was able to induce antigen-specific tolerance mediated by Foxp3+ regulatory T cell (Treg) that function in an IL-10 and transforming growth factor (TGF)-β-dependent mechanism [35]
Summary
The mucosal immune system in close interaction with symbiotic bacteria is constantly working to maintain a homeostatic balance between immune activation, which is necessary against vast amounts of exogenous antigens and noxious stimuli, and immune tolerance toward harmless inhaled or ingested antigens and the host microbiota. Inducible gene expression allows control of therapeutic drug delivery; additional genetic engineering may hamper clinical use of the L. lactis strains. These bacteria can secrete the soluble protein low-calcium response V antigen (LcrV) that stimulates host-IL-10 production which in turn will facilitate bacterial survival through its anti-inflammatory effects, on IFN-γ [61].
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