The immune system delicately balances immunity against threats and tolerance to self-proteins. A dysfunction in this balance often leads to illnesses such as cancer, autoimmune diseases, and life-threatening allergies. As rates of autoimmune disease and allergy rise, the need for effective treatments becomes urgent. The current standard of care involves systemic immune suppression that puts the patient at risk for opportunistic infections. Consequently, a major goal of immunotherapy is to generate antigen-specific tolerance to only the antigen or antigens causing disease. Our lab has previously provided evidence that antigen delivered to and processed via endogenous pathways in the liver can result in antigen-specific T cell tolerance both in prophylactic and therapeutic settings. It was also shown that liver sinusoidal endothelial cells (LSECs) are the major hepatic cells that play an active role in the liver’s mechanisms for inducing antigen-specific tolerance. In this project, we aim to test the boundaries of our current technologies in autoimmune disease models that rely on B cell responses. We also aim to understand endogenous pathways to design the next generation of therapeutics. In this thesis, I investigate two approaches to generate antigen-specific tolerance by using endogenous pathways in the liver. The first approach uses a mouse model to test the in vivo feasibility of a glycopolymer-conjugated antigen in preventing a B cell-mediated autoimmune disease. The second approach furthers the development of an LSEC-specific promoter to modify LSEC gene expression in vivo using a lentiviral delivery method. This tool can probe the cellular pathways involved in LSEC antigen presentation and tolerance induction by knocking down or modulating gene expression related to antigen presentation and tolerance.