In autoimmune diseases, the immune system mistakenly identifies “self”-molecules/antigens as foreign, resulting
in an orchestrated attack of the body. In multiple sclerosis (MS), the immune system attack of the protective neuronal sheath
– myelin - results in debilitating neurological impairment and poor quality of life. Current MS therapies are non-curative,
require life-long compliance, and exhibit non-specific effects that increase patient susceptibility to infection. To circumvent
MS treatment challenges, emerging therapies seek to direct myelin self-antigens (MOG) and immunomodulatory cues to
redirect the immune response. Toll-like receptors, which detect pathogen-associated patterns on antigen presenting cells
(APCs) are involved in MS. Recently, TLR9 antagonist, GpG has been shown to downregulate APC activation while
promoting TREGS. Similarly, Rapamycin (Rapa), an immunosuppressant drug has garnered interest because it inhibits major
pathways and promotes regulatory T cells (TREGS). Since coordination between the innate and adaptive immune system in
MS drives disease, the proposed study will target these pathways simultaneously to promote antigen-specific immune
tolerance in MS.
We have previously developed self-assembled carriers built entirely from immune cues – termed immune
polyelectrolyte multilayers (iPEMs) that enable combinatory delivery of multiple cues, controlled loading, and high cargo
densities. iPEMs assembled using MOG and GpG reduce TLR9 signaling while promoting TREGS but show moderate
efficacy in preclinical MS models. Since TREGS play a crucial role in moderating immune responses, the proposed work aims
to load Rapa in the core of MOG/GpG iPEMs to enable co-delivery of MOG to induce antigen-specific immune responses,
GpG to downregulate APC activity, and incorporate cross-links to control Rapa delivery to induce TREGS. In Aim 1, the
hypothesis that cross-link density in MOG/GpG (Rapa) iPEMs is correlated to release intervals will be tested. This will be
accomplished by generating a library of iPEMs from combinations of MOG, control antigen (ANT-CTRL), GpG, inactive
control ODN (ODNCTRL), as well as Rapa with distinct cross-linking conditions to control release. In Aim 2, cross-linked
iPEM release kinetics will be linked to APC activation and T cell polarization. In Aim 3, the efficacy of crosslinked iPEMs
in preclinical MS models will be assessed to test the hypothesis that dual-targeting of innate and adaptive immunity is
necessary to drive antigen-specific TREGS in MS. These studies will show that modulating both innate and adaptive immunity
is necessary to generate robust antigen-specific responses in MS and will provide insight that informs the design of new
therapies to treat MS and other autoimmune diseases. At the same time, new skills and techniques will be acquired
throughout the course of the studies to propel the goal of the trainee to lead an academic research lab focused on developing
immunomodulatory drug delivery systems after postdoctoral training.