Modulating innate signaling in skin antigen presenting cells using microneedles to promote antigen-specific tolerance in autoimmunity — ASN Events
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  2. Poster Session 2
  3. Modulating innate signaling in skin antigen presenting cells using microneedles to promote antigen-specific tolerance in autoimmunity

Modulating innate signaling in skin antigen presenting cells using microneedles to promote antigen-specific tolerance in autoimmunity (#220)

Valinteshley D. Pierre 1 , Robert S. Oakes 2 3 , Shrey A. Shah 1 4 , Emma R. Brannon 1 , Christine P. Carney 1 , Senta M. Kapnick 1 3 , Christopher M. Jewell 1 3 5 6
  1. Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, College Park, Maryland, United States
  2. Biomedical Engineering, University of Delaware, Newark, Delaware, United States
  3. Veterans Affairs Maryland Health Care System, United States Department of Veterans Affairs, Baltimore, Maryland, United States
  4. Fischell Department of Bioengineering, University of Maryland, College Park, College Park, Maryland, United States
  5. Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, College Park, Maryland, United States
  6. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States

Motivation: Autoimmunity is a condition where the immune system mistakenly attacks host tissue. Innate signaling in immune cells has historically been associated with response to danger signals, pathogens, and injury through pattern recognition receptors. However, recent studies increasingly show that innate signaling through toll-like receptors (TLRs) in antigen presenting cells (APCs), such as dendritic cells (DCs), is implicated in initiating, amplifying, and sustaining autoimmune pathology. Thus, TLRs are emerging as new therapeutic targets for selective tolerance. Furthermore, the skin is densely populated with APCs that traffic to draining lymph nodes where they crosstalk with the adaptive immune system to induce antigen-specific T cell tolerance. We reasoned that microneedle arrays (MNAs) can deliver self-antigen and immunomodulatory cues to the skin to modulate innate signaling in APCs to drive systemic tolerance. Methods: MNAs were loaded with self-antigen (myelin oligodendrocyte glycoprotein; MOG) and TLR antagonists, GpG. In vitro, isolated bone marrow-derived DCs (BMDCs) were treated with MOG/GpG complexes to evaluate co-stimulatory markers, innate pathway activation, and cytokine secretion. To confirm antigen specificity, BMDCs were co-cultured with autoreactive T cells and evaluated for regulatory T cell (TREG) expansion. Finally, MOG/GpG-loaded MNA treatment efficacy was evaluated in a mouse model of MS. Results: DCs treated with MNA in vivo and in vitro internalized MOG/GpG complexes, modulated downstream innate signaling, reduced autoreactive T cells, and expanded antigen-specific TREG in primary cell cultures. Diseased mice treated with MNA reduced peak clinical score, induced regulatory gene expression, and expanded antigen-specific TREGS. Furthermore, MNA treatment modulated co-stimulatory markers and increased regulatory cytokine secretion in DCs. Conclusion: These studies show that targeting innate signaling in skin APCs with MNA promotes systemic antigen-specific tolerance in mouse autoimmunity. This work further supports skin as an emerging therapeutic target for autoimmune therapies.