Event

PhD Dissertation Defense - Shrey Shah

Friday, December 13, 2024
12:00 p.m.
KEB 1107 (Kim Engineering Building)
Rachel Chang
301 405 8268
rachel53@umd.edu

Title: Design of microneedle arrays to target and train innate immune cells in the skin to combat autoimmunity

Committee members:

Dr. Christopher Jewell, Chair

Dr. Jonathan Bromberg

Dr. Gregg Duncan

Dr. Xiaoming “Shawn” He

Dr. Ryan Sochol, Dean's Representative

Abstract:

Autoimmune diseases, such as multiple sclerosis (MS), type 1 diabetes, and lupus, affect at least 50 million people in the United States. In healthy individuals, immune tolerance protects against attacks on host tissues. However, during autoimmune diseases like MS, dysfunctional immune cells target host self-molecules known as self-antigens, leading to inflammation and tissue damage. Currently, there are no cures for these diseases, and existing therapies are non-specific, leaving patients vulnerable to immunosuppressive side effects. An experimental approach to treating autoimmune diseases involves promoting tolerance specifically to self-antigens—for instance, myelin in MS—while preserving normal immune function. One strategy to achieve this is by co-delivering self-antigens with immune signals that influence specific cellular pathways in specialized innate immune cells called dendritic cells (DCs). DCs, which are highly concentrated in the skin play a crucial role in mediating immune responses. These cells can migrate to specialized immune organs, such as lymph nodes, to help redirect self-reactive immune cells, such as T cells, away from inflammatory responses and toward regulatory phenotypes.

The work presented in this dissertation explores how DCs in the skin can be exploited to promote immune tolerance to combat autoimmune disease. First, the data from the dissertation demonstrates that innate immune signaling pathways, such as the toll-like receptor (TLR) pathway, can be harnessed to promote functional tolerogenic phenotypes in DCs in vitro. These generated tolerogenic DCs can suppress T-cell proliferation and promote regulatory phenotypes in T cells. The data provides knowledge to help generate tolerogenic DCs by utilizing innate immune signaling pathways, informing the design of next-generation immunotherapies for autoimmune disease. Next, to test if in vitro findings can be utilized to promote immune tolerance in preclinical animal models, I designed specialized biomaterials – microneedle arrays (MNAs) – to deliver self-antigen and innate immune cues to the DCs in the skin. The designed MNAs promote tolerogenic features in innate immune cells in the skin, including DCs, and promote antigen-specific immune tolerance in mouse models of MS.  Moreover, the designed MNAs provide cargo stability at shipping conditions and are modular, allowing for the loading of multiple and different types of cargo. This modularity allows for delivering both existing drugs and novel immunotherapies using MNAs to fight autoimmune disease.

My dissertation provides insights into using the skin and its immune cells to induce antigen-specific immune tolerance for treating autoimmune diseases. Key contributions include advancing the understanding of tolerogenic dendritic cell biology, particularly the role of innate immune signaling and PRRs in promoting tolerogenic DC phenotypes—knowledge that could guide new cell-based autoimmune therapies and broaden immunological understanding. Additionally, my work explores the largely untapped potential of MNAs in autoimmunity, establishing design and delivery principles for MNA-based systems that target skin to achieve antigen-specific immune tolerance.