Lymph node depots control T cell fate to safely and durably reverse myelin-driven autoimmunity

Saturday, October 11, 2025

3:00 PM - 3:15 PM PDT

Location: Room 32A

Presenting Author(s)

Senta Kapnick, PhD

Associate Research Scientist
Robert E. Fischell Institute for Biomedical Devices/University of Maryland; Veterans Affairs MD Healthcare System/Department of Veterans Affairs, United States

Co-Author(s)

EG

Emily Gosselin

Fischell Department of Bioengineering/University of Maryland, United States
ST

Shannon Tsai

Fischell Department of Bioengineering/University of Maryland, United States
Robert Oakes

Assistant Professor
University of Delaware, Delaware, United States
MA

Marian Ackun-Farmmer

Principal Investigator
Georgia Institute of Technology, United States
Sean T. Carey

Fischell Department of Bioengineering/University of Maryland, United States
Shrey Shah, PhD

Graduate Student
Fischell Department of Bioengineering/University of Maryland, United States
RS

Ruochen Shen

PhD Student
Fischell Department of Bioengineering/University of Maryland
College Park, Maryland, United States
CB

Christopher Bridgeman

Graduate Student
University of Maryland- College Park, Maryland, United States
Ryan McIlvaine

Graduate Student
Fischell Department of Bioengineering/University of Maryland, United States
LT

Lisa H. Tostanoski

Fischell Department of Bioengineering/University of Maryland, United States
RP

Richard Pierson

Department of Surgery/Massachusetts General Hospital, United States
JB

Jonathan Bromberg

Department of Surgery/University of Maryland School of Medicine, United States

Last Author(s)

Christopher Jewell

Professor
Robert E. Fischell Institute for Biomedical Devices/University of Maryland; Veterans Affairs MD Healthcare System/Department of Veterans Affairs, United States

Primary Investigator(s)

Christopher Jewell

Professor
Robert E. Fischell Institute for Biomedical Devices/University of Maryland; Veterans Affairs MD Healthcare System/Department of Veterans Affairs, United States

Introduction: : Multiple sclerosis (MS) is an inflammatory autoimmune disease that occurs when lymphocytes mistakenly attack myelin, resulting in motor deficits and cognitive deterioration. Existing therapies are non-curative and hindered by dose-limited toxicity and off-target effects that can leave patients vulnerable to opportunistic infections or interfere with vaccination. We devised a strategy to induce antigen-specific immune tolerance (ASIT) to combat autoimmunity in preclinical models of MS. This technology exploits local delivery of diffusion-limited polymer scaffolds loaded with self-antigen and a tolerizing cue to lymph nodes (LNs). Because depots are too large to diffuse out after injection, release of cargo creates local niches that guide T cell fates in treated LNs. The development of antigen-specific therapies could offer disruptive outcomes for patients with MS by overcoming limitations of existing treatments and achieving remission without impacting healthy immune surveillance.

Materials and

Methods: : Poly(lactide-co-glycolic acid) depots loaded with peptide and Rapamycin (Rapa) were produced using double emulsion synthesis and delivered directly to LNs by tracer-guided injection. Experimental autoimmune encephalomyelitis (EAE) was induced with myelin peptides and adjuvant. Vaccine challenge was performed with ovalbumin protein (OVA) and CpG adjuvant using a prime/boost strategy. Adoptive transfers were coupled with flow cytometry, immunofluorescence microscopy, and RT-qPCR to assess T cell/tissue phenotypes, antigen-specificity, and function.

Results, Conclusions, and Discussions:: In multiple preclinical MS mouse models, a single administration to LNs of depots loaded with myelin peptide and a tolerizing cue (Rapa) induced durable, potent efficacy during i) early therapeutic, ii) peak (Fig. 1A) or iii) late-stage disease. Efficacy was accompanied by generation of Tregs in response to depot-derived regulatory cues through mechanisms that include i) polarization of naive T cells (Fig. 1B), and ii) re-polarization of previously activated, inflammatory T cells (i.e., transdifferentiation). Transcriptional analysis revealed altered signaling pathways that directly control T cell trafficking associated with elimination of lesions in spinal cords (Fig. 1C). Importantly, this therapy does not interfere with healthy antigen-specific T and B cell responses in response to vaccine challenge (Fig. 1D). Finally, LN depots offer an attractive chemistry and manufacturing control (CMC) profile and favorable safety outcomes in non-human primates including normal blood chemistry, liver and kidney function.

Allergic sensitization and new clinical trials are bringing awareness to the benefits of direct lymph node injections for immunotherapy. Here, we show that coupling this strategy with degradable polymer depots programs antigen-specific regulatory T cells to induce safe, potent, and durable tolerance for treating myelin-driven autoimmunity. These findings provide insight into mechanisms that could advance therapeutic formulations that potentially eliminate the need for repeated or systemic administration, and are more likely to succeed in MS clinical trials or be expanded for applicability to other autoimmune diseases.

Acknowledgements and/or References (Optional)::