Event

Title: Exploiting Local Immune Niches to Promote Durable and Selective Tolerance During Type 1 Diabetes

Committee members:
Dr. Christopher Jewell, Chair
Dr. Jonathan Bromberg
Dr. Gregg Duncan
Dr. Katharina Maisel
Dr. David Mosser, Dean's Representative

Abstract:
Autoimmune disease occurs when the homeostasis of healthy immunity is disrupted and results in the destruction of host tissue. During Type 1 Diabetes, this autoimmune response results in the attack of pancreatic islets—key tissues that produce insulin—ultimately resulting in the loss of blood glucose control and associated co-morbidities including cardiovascular disease and stroke. Immune responses, including autoimmunity, are organized in immune tissues called lymph nodes. At these sites, antigens are presented to T and B cells, activating them before they migrate to sites of infection and disease. The integration of antigen and immune cues in lymph nodes directs the type of immune response toward either inflammation or immune tolerance—where host tissues are protected rather than destroyed. An unmet need in autoimmune disease is targeted treatments that prevent autoinflammatory cells from damaging tissues without impacting healthy cell populations.  One emerging therapeutic paradigm for autoimmunity and inflammatory diseases is the induction of antigen-specific immune tolerance. This approach would selectively protect self-tissue without impacting healthy immune cells, thus preserving normal immune responses to vaccines and infection. While exciting, antigen-specific immune tolerance has yet to be achieved in patients with autoimmune disease.
This dissertation describes a materials-based strategy to durably alter the lymph node niche for immune tolerance. In this work, I show that distinct immune cues can be co-encapsulated with autoantigen into degradable microparticles, then directly injected into lymph nodes. These particles are too large to drain from lymph nodes, instead releasing cargo over time. I show that this approach combats several core models of islet autoimmunity, including a challenging, spontaneous model of diabetes. Notably, I expand on our understanding of the mechanism of this platform through key studies interrogating sub-populations of T cells. I demonstrate that treatment promotes the expansion of long-lived, potent regulatory cells that persist long after initial treatment. The work in this dissertation provides increased understanding of how materials can be used to control immune responses, as well as better understand the mechanisms of protection from materials approaches to autoimmunity. Additionally, the knowledge generated will contribute to the development of next-generation long-lasting immunotherapies.