A Novel Tolerance inducing Probiotic Platform

Project Summary Our goal is to validate a novel Lactococcus lactis L lactis based platform to rapidly develop and deliver tolerance inducing therapeutics for the treatment of autoimmunity and allergy Autoimmune and allergic diseases such as Multiple Sclerosis MS Type Diabetes and food allergies affect of the world population and are continuing to rise These illnesses are the result of the loss of tolerance to self or environmental antigens and cause symptoms ranging from minor irritation to debilitation or death For successful induction of immune tolerance mucosal tissues play a significant role The epithelial layers that cover the Gut Associated Lymphoid Tissue GALT and Nasopharyngeal Associated Lymphoid Tissue NALT areas contain a subpopulation of specialized cells microfold or M cells that sample environmental antigens and present them to the adjacent immune cells A number of studies now confirm that these cells play a crucial role in the generation of tolerance to a given antigen Reoviruses are segmented double stranded RNA viruses that bind and infect humans via mucosal surfaces using the viral coat protein p We have demonstrated that fusion proteins consisting of p fused to an antigen of choice can bind to M cells and generate a tolerogenic immune response to that antigen The ability of p antigen targeting to induce tolerance has been demonstrated in both allergy and autoimmune models including the mouse experimental autoimmune encephalomyelitis EAE model of MS and oral allergy The tolerance response is antigen specific and due to the induction of anti inflammatory cytokines and an increase in suppressive regulatory T cells Tregs While lactic acid bacteria LABs are traditionally used for food production and their probiotic properties genetically engineered LABs have been produced by us and others to deliver immune modulators to the host mucosa To reduce the complexity and cost associated with producing therapeutic recombinant p based proteins carrying multiple antigens and to improve the mucosal pharmacokinetic and pharmacodynamic PK PD properties following oral administration our strategy is to deliver p based proteins in the context of L lactis We believe L lactis represents an ideal delivery system as it has Generally Regarded as Safe GRAS status by the FDA and is widely used in food applications This proposal is designed to validate a novel L lactis platform LacP for rapid development and delivery of p targeted immune modulators At the same time we will also validate the first therapeutic candidate using this platform for the treatment of MS The specific aims are to develop an L lactis strain expressing a p fusion protein containing three dominant MS auto antigens VTC demonstrate that oral administration of VTC prevents neurological symptoms in the mouse EAE model and confirm that VTC induces Tregs while reducing antibody levels in the EAE model Project Narrative Autoimmunity and food allergies are a major health concern worldwide particularly in western countries with symptoms ranging from mild irritation to severe reactions including debilitation or death This project aims to develop a novel flexible platform for the delivery of a broad range of tolerance therapeutics Successful completion of this proposal will lead to a novel platform for rapid development of oral based tolerance therapies as well as validation of the first therapeutic candidate for the treatment of MS