Towards programming immune tolerance through geometric manipulation of phosphatidylserine.
The possibility of engineering the immune system in a targeted fashion using biomaterials such as nanoparticles has made considerable headway in recent years. However, little is known as to how modulating the spatial presentation of a ligand augments downstream immune responses. In this report we show that geometric manipulation of phosphatidylserine (PS) through fabrication on rod-shaped PLGA nanoparticles robustly dampens inflammatory responses from innate immune cells while promoting T regulatory cell abundance by impeding effector T cell expansion. This response depends on the geometry of PS presentation as both PS liposomes and 1 micron cylindrical PS-PLGA particles are less potent signal inducers than 80 × 320 nm rod-shaped PS-PLGA particles for an equivalent dose of PS. We show that this immune tolerizing effect can be co-opted for therapeutic benefit in a mouse model of multiple sclerosis and an assay of organ rejection using a mixed lymphocyte reaction with primary human immune cells. These data provide evidence that geometric manipulation of a ligand via biomaterials may enable more efficient and tunable programming of cellular signaling networks for therapeutic benefit in a variety of disease states, including autoimmunity and organ rejection, and thus should be an active area of further research.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Reid A
RA
Roberts
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Timothy K
TK
Eitas
Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
James D
JD
Byrne
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Brandon M
BM
Johnson
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Patrick J
PJ
Short
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Karen P
KP
McKinnon
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Shannon
S
Reisdorf
Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Christopher
JC
Luft
Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA.|Sloan-Kettering Institute for Cancer Research, Memorial Sloan Kettering Comprehensive Cancer Center, New York, NY 10065, USA.
Joseph M
JM
DeSimone
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Institute for Inflammatory Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jenny P
JP
Ting
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000473:pathology; D015536:Down-Regulation; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism; D043942:Nanotubes; D052638:Particulate Matter / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry* / Q000378:metabolism*
D016207:Cytokines; D052638:Particulate Matter; D010718:Phosphatidylserines
Autoimmunity; Immunoengineering; Immunomodulation; Nanoparticles; PLGA; PRINT; Phosphatidylserine; Tolerance; Transplantation