UC San Diego

Chronic autoimmune disorders collectively affect 5-7% of the global population and are a major public health concern. The prevailing paradigm for autoimmune disease treatment relies on immunosuppression, which can be effective but leaves patients susceptible to opportunistic or serious infections and cancer. Moreover, these therapies are not designed to correct immune dysfunction that underlies autoimmunity. For those that continue to experience disease symptoms, there is an unmet need for therapies that operate via immunoregulation and avoid generalized immunosuppression. A key challenge is that unlike diseases with known etiology, the pathogenesis of autoimmune diseases can be complex. However, a common feature involves hyperactivated immune cells that, left unchecked, can lead to permanent damage of healthy tissue. To this end, a key defect arises from a loss in the number and function of autoimmune-protective cells called regulatory T cells (Treg) that normally prevent immune responses against one’s own cells and tissues. The premise of this dissertation is that enhancing Treg can be harnessed to promote disease-specific immunoregulation without causing generalized immunosuppression. To test the premise, the work reported herein describes the development and applications of biomaterial-based disease modifying agents. Three methods are described. The first method described used an immunomodulatory nanocomplex formulation that differentially modulated immune cell metabolism to enhance Treg over inflammatory T cells. A kinetic model describing Treg enhancement confirmed a strong dependence on the initial T cell population. The second and third methods described demonstrated that the epigenetic modulation of immune cells can strongly influenced the immunophenotypic trajectories of T cells that favor a Treg phenotype. Further, the formulation of a novel sustained biomaterial designed to locally enhance Treg via epigenetic modulation and its application in a model of inflammatory arthritis is reported. Overall, this work paves the way for the systematic design and validation of immunoregulatory biomaterials for the treatment of autoimmune disorders.