The Woodruff School

SUMMARY

https://primetime.bluejeans.com/a2m/live-event/kjykpttp Traditional pharmaceutical and biological treatments suffer from shortcomings in the treatment of autoimmune diseases such as Multiple Sclerosis (MS) due to being non-specific, systemic, and causing serious side effects such as complete immunosuppression and increased risk of other pathologies. Recently, the use of dendritic cells (DCs) as a cell therapy to treat autoimmunity has been investigated, but inadequate delivery to the target site and cell activation due to widespread inflammation has limited their efficacy. To overcome these limitations, biophysical and biochemical cell-biomaterial interactions between DCs and 4-arm maleimide functionalized poly(ethylene glycol) (PEG-4MAL) hydrogels were characterized and hydrogels were optimized to support viability and immaturity in encapsulated DCs. PEG-4MAL hydrogels were subsequently functionalized with modified IL-10, which resulted in prolonged support and protection against inflammation. In a murine model of MS, prophylactic treatment with DCs delayed the onset of symptoms in mice, regardless of delivery method. However, hydrogel-delivered DCs significantly ameliorated symptoms of paralysis compared to therapeutic DCs injected subcutaneously, indicating a more durable tolerogenic response. Post-processing of murine tissues and in vitro co-culture studies showed marked infiltration of endogenous lymphocytes into the immunosuppressive biomaterial niche, where DCs tolerize host cells through induction of CD25+FoxP3+ T regulatory cells (Tregs) and exhaustion of CD8+ T cells mediated by programmed cell death protein 1 (PD-1). A significant reduction of maturation markers amongst CD11b+ APCs in the CNS illustrates that the immunomodulatory effects of this treatment reach the anatomical site of injury. Overall, these results suggest that the tolerogenic biomaterial delivery system developed herein significantly improves the robustness of a DC therapy in a mouse model of MS. Additionally, the DC-biomaterial interactions characterized herein accentuate the flexibility in tuning PEG-4MAL hydrogels for other tolerogenic applications.

SUBJECT:	Ph.D. Dissertation Defense

BY:	Nicholas Beskid

TIME:	Thursday, July 23, 2020, 11:00 a.m.

PLACE:	Virtual, Virtual

TITLE:	Functionalized PEG-4MAL Hydrogels for Delivery of Dendritic Cells in Tolerogenic Applications

COMMITTEE:	Dr. Julie Babensee, Chair (BME) Dr. Andres Garcia (ME) Dr. Susan Thomas (ME) Dr. Edward Botchwey (BME) Dr. Jacob Kohlmeier (Emory)

SUMMARY https://primetime.bluejeans.com/a2m/live-event/kjykpttp Traditional pharmaceutical and biological treatments suffer from shortcomings in the treatment of autoimmune diseases such as Multiple Sclerosis (MS) due to being non-specific, systemic, and causing serious side effects such as complete immunosuppression and increased risk of other pathologies. Recently, the use of dendritic cells (DCs) as a cell therapy to treat autoimmunity has been investigated, but inadequate delivery to the target site and cell activation due to widespread inflammation has limited their efficacy. To overcome these limitations, biophysical and biochemical cell-biomaterial interactions between DCs and 4-arm maleimide functionalized poly(ethylene glycol) (PEG-4MAL) hydrogels were characterized and hydrogels were optimized to support viability and immaturity in encapsulated DCs. PEG-4MAL hydrogels were subsequently functionalized with modified IL-10, which resulted in prolonged support and protection against inflammation. In a murine model of MS, prophylactic treatment with DCs delayed the onset of symptoms in mice, regardless of delivery method. However, hydrogel-delivered DCs significantly ameliorated symptoms of paralysis compared to therapeutic DCs injected subcutaneously, indicating a more durable tolerogenic response. Post-processing of murine tissues and in vitro co-culture studies showed marked infiltration of endogenous lymphocytes into the immunosuppressive biomaterial niche, where DCs tolerize host cells through induction of CD25+FoxP3+ T regulatory cells (Tregs) and exhaustion of CD8+ T cells mediated by programmed cell death protein 1 (PD-1). A significant reduction of maturation markers amongst CD11b+ APCs in the CNS illustrates that the immunomodulatory effects of this treatment reach the anatomical site of injury. Overall, these results suggest that the tolerogenic biomaterial delivery system developed herein significantly improves the robustness of a DC therapy in a mouse model of MS. Additionally, the DC-biomaterial interactions characterized herein accentuate the flexibility in tuning PEG-4MAL hydrogels for other tolerogenic applications.