Local control of T cell fate in lymph nodes safely and durably reverses myelin-driven autoimmunity
Development of tolerogenic, antigen-specific immunotherapies could overcome limitations of existing treatments for inflammatory autoimmune diseases by achieving potent, durable remission without impacting healthy immune surveillance. Here, we deliver diffusion-limited polymer depots to lymph nodes to locally guide T cell fates for the treatment of multiple sclerosis (MS), an autoimmune disease that occurs when the immune system mistakenly attacks myelin. In preclinical MS models, depots loaded with myelin self-antigen and tolerizing cues mediate localized retention of activated CD4 T cells, promote myelin-specific regulatory T cells, and reshape inflammation in the central nervous system (CNS) to eliminate lesions. Selective disease reversal is achieved with a single treatment that induces long-lasting remission without hindering healthy responses to vaccine challenge with foreign antigen. Furthermore, depots offer favorable chemistry and manufacturing control features and are well tolerated in non-human primates. This work supports a clinically feasible concept for inducing safe, effective, antigen-specific tolerance without systemic or repeated dosing.
Authors
- Christopher J. Bridgeman
- Maeesha Noshin
- Agnes M. Azimzadeh (ORCID: https://orcid.org/0000-0003-0761-6353)
- Lisa H. Tostanoski (ORCID: https://orcid.org/0000-0001-9255-5684)
- Marian A. Ackun‐Farmmer (ORCID: https://orcid.org/0000-0003-3081-5115)
- Ruochen Shen (ORCID: https://orcid.org/0000-0001-9967-4758)
- Zahra Habibabady (ORCID: https://orcid.org/0000-0002-3314-3716)
- Emily A. Gosselin (ORCID: https://orcid.org/0000-0002-1177-0153)
- Sean T. Carey (ORCID: https://orcid.org/0000-0003-1851-0300)
- Shannon J. Tsai
- Eugene Froimchuk
- Robert S. Oakes (ORCID: https://orcid.org/0000-0003-3783-6488)
- Jonathan S. Bromberg (ORCID: https://orcid.org/0000-0002-1407-8795)
- Sheneil K. Black (ORCID: https://orcid.org/0009-0000-9208-7534)
- Haleigh B. Eppler (ORCID: https://orcid.org/0000-0001-6332-3331)
- Christopher M. Jewell (ORCID: https://orcid.org/0000-0002-6668-6928)
- Alexis A. Yanes
- Senta M. Kapnick (ORCID: https://orcid.org/0000-0002-2246-7053)
- Shrey Shah (ORCID: https://orcid.org/0000-0001-7037-6845)
- Richard N. Pierson
- Xiangbin Zeng
- Ryan A. McIlvaine (ORCID: https://orcid.org/0000-0002-6115-1350)
Institutions
- University of Maryland, Baltimore (US)
- Massachusetts General Hospital (US)
- Vince Lombardi Cancer Clinic (US)
- Department of Veterans Affairs (AU)
- VA Maryland Health Care System (US)
- University of Baltimore (US)
- University of Maryland, College Park (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1073/pnas.2409563122
- Citations
- 2
- Primary Topic
- Multiple Sclerosis Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.94
Funders
- National Science Foundation
- U.S. Department of Veterans Affairs
- Massachusetts General Hospital
- University of Maryland
- National Institutes of Health
- A. James Clark School of Engineering
- National Cancer Institute