Engineering the lymph node environment promotes antigen-specific efficacy in type 1 diabetes and islet transplantation

Joshua M. Gammon, Sean T. Carey, Vikas Saxena, Haleigh B. Eppler, Shannon J. Tsai, Christina Paluskievicz, Yanbao Xiong, Lushen Li, Marian Ackun-Farmmer, Lisa H. Tostanoski, Emily A. Gosselin, Alexis A. Yanes, Xiangbin Zeng, Robert S. Oakes, Jonathan S. Bromberg () and Christopher M. Jewell ()
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Joshua M. Gammon: University of Maryland, College Park
Sean T. Carey: University of Maryland, College Park
Vikas Saxena: University of Maryland Medical School
Haleigh B. Eppler: University of Maryland, College Park
Shannon J. Tsai: University of Maryland, College Park
Christina Paluskievicz: University of Maryland Medical School
Yanbao Xiong: University of Maryland Medical School
Lushen Li: University of Maryland Medical School
Marian Ackun-Farmmer: University of Maryland, College Park
Lisa H. Tostanoski: University of Maryland, College Park
Emily A. Gosselin: University of Maryland, College Park
Alexis A. Yanes: University of Maryland, College Park
Xiangbin Zeng: University of Maryland, College Park
Robert S. Oakes: University of Maryland, College Park
Jonathan S. Bromberg: University of Maryland Medical School
Christopher M. Jewell: University of Maryland, College Park

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation.

Date: 2023
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DOI: 10.1038/s41467-023-36225-5

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