Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific.
Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells toward tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin) permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the CNS. Our findings suggest that local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic but antigen specific.
Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
Lisa H
LH
Tostanoski
Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
Yu-Chieh
YC
Chiu
Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
Joshua M
JM
Gammon
Department of Surgery, University of Maryland School of Medicine, 29 South Greene Street, Baltimore, MD 21201, USA; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, MD 21201, USA.
Thomas
T
Simon
Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
James I
JI
Andorko
Department of Surgery, University of Maryland School of Medicine, 29 South Greene Street, Baltimore, MD 21201, USA; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, MD 21201, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA.
Jonathan S
JS
Bromberg
Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA; United States Department of Veteran Affairs, 10 North Greene Street, Baltimore, MD 21201, USA. Electronic address: cmjewell@umd.edu.
Christopher M
CM
Jewell
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007267:Injections; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009186:Myelin Sheath; D063308:Myelin-Oligodendrocyte Glycoprotein; D010641:Phenotype; D011108:Polymers; D020123:Sirolimus / Q000494:pharmacology
D001324:Autoantigens; D000939:Epitopes; D063308:Myelin-Oligodendrocyte Glycoprotein; D011108:Polymers; D020123:Sirolimus
CNS; autoimmunity; biomaterial; immune tolerance; lymph node; microparticle; multiple sclerosis; nanoparticle; regulatory T cell; vaccine