PROJECT SUMMARY: During autoimmunity, the body incorrectly identifies “self” molecules as foreign. In
multiple sclerosis (MS) attack of myelin in the central nervous system (CNS) leads to neurodegeneration. Existing
therapies for MS range from immunosuppressants to newer monoclonal antibodies, but even the latter do not
distinguish between healthy and self-reactive cells displaying the antibody target. Thus, while beneficial, existing
therapies are not curative, cause immunocompromising side effects, and require life-long compliance. These
limitations have motivated efforts to control autoimmunity with vaccine-like specificity, leaving the rest of the
immune system intact. One such antigen-specific tolerance strategy being studied pre-clinically and in human
trials is co-delivery of myelin peptide and tolerizing immune signals to promote populations, such as regulatory
T cells (TREG) that combat MS. The polarization of T cells into inflammatory T cells (e.g., TH17) or TREG is localized
to lymph nodes (LNs), tissues that coordinate immunity. New studies also reveal TREG can adopt memory
functions to maintain tolerance. Further, in appropriate tissue niches, inflammatory TH17 cells can
transdifferentiate to TREG. Likewise, B cells are relevant to MS in several ways, including producing pathogenic
myelin-specific antibodies, and as therapeutic targets able to adopt regulatory function. LNs play key roles in
these processes, directing dynamic stromal organization to promote and regulate cell interaction and modulatory
cues that control T and B cell polarization between (auto)inflammatory and tolerance functions. From a
therapeutic view, controlling this niche is challenging using conventional delivery technologies (e.g., systemic
injections/infusions), and even biomaterial approaches such as targeted nanoparticles face difficulty establishing
durable tissue environments after injection. However, the ability to understand and control the integration of
signals in the LN microenvironment could enable potent, myelin-specific immunotherapies that avoid
immunosuppression. We propose tackling this goal using a platform that combines direct intra-LN (i.LN.) injection
with controlled release biomaterial depots. We have shown diffusion-restricted polymer depots that are too large
to drain from LNs after injection concentrate and retain depot-loaded cargo in LNs. Using depots loaded with
myelin peptide and rapamycin - an immunoregulatory drug, we have shown a single treatment at the peak of
disease in a pre-clinical model of MS reverses paralysis for over 90 days. Efficacy is not achieved with i.LN.
injection of soluble cargo, or during injection of depots via traditional routes. We will use this interdisciplinary
immune engineering approach to understand how local controlled release promotes a tolerogenic stromal LN
environment and how these effects induce and maintain long-lasting tolerizing function against myelin in T and
B cells. The aims are 1) Define the robustness of efficacy and the underpinning therapeutic effects on
neuroinflammation, 2) Show the durability of tolerance is antigen-dependent and driven by TREG maintenance &
plasticity, 3) Show i.LN. depots disrupt germinal centers, reduce auto-antibodies, & induce tolerogenic B cells.
