title: Tolerance induction using nanoparticles bearing HY peptides in bone marrow transplantation.
abstract: Allogeneic cell therapies have either proven effective or have great potential in numerous applications, though the required systemic, life-long immunosuppression presents significant health risks. Inducing tolerance to allogeneic cells offers the potential to reduce or eliminate chronic immunosuppression. Herein, we investigated antigen-loaded nanoparticles for their ability to promote transplant tolerance in the minor histocompatibility antigen sex-mismatched C57BL/6 model of bone marrow transplantation. In this model, the peptide antigens Dby and Uty mediate rejection of male bone marrow transplants by female CD4+ and CD8+ T cells, respectively, and we investigated the action of nanoparticles on these T cell subsets. Antigens were coupled to or encapsulated within poly(lactide-co-glycolide) (PLG) nanoparticles with an approximate diameter of 500 nm. Delivery of the CD4-encoded Dby epitope either coupled to or encapsulated within PLG particles prevented transplant rejection, promoted donor-host chimerism, and suppressed proliferative and IFN-γ responses in tolerized recipients. Nanoparticles modified with the Uty peptide did not induce tolerance. The dosing regimen was investigated with Dby coupled particles, and a single dose delivered the day after bone marrow transplant was sufficient for tolerance induction. The engraftment of cells was significantly affected by PD-1/PDL-1 costimluation, as blockade of PD-1 reduced engraftment by ∼50%. In contrast, blockade of regulatory T cells did not impact the level of chimerism. The delivery of antigen on PLG nanoparticles promoted long-term engraftment of bone marrow in a model with a minor antigen mismatch in the absence of immunosuppression, and this represents a promising platform for developing a translatable, donor-specific tolerance strategy.
authors.affiliation: Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd / E310, Evanston, IL 60208, USA; Simpson Querrey Institute for BioNanoTechnology (SQI), Northwestern University, Chicago, IL 60611, USA.
authors.forename: Kelan A
authors.initials: KA
authors.lastname: Hlavaty
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 300 E Superior St, Chicago, IL 60611, USA.
authors.forename: Derrick P
authors.initials: DP
authors.lastname: McCarthy
authors.affiliation: Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
authors.forename: Eiji
authors.initials: E
authors.lastname: Saito
authors.affiliation: Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd / E310, Evanston, IL 60208, USA; Simpson Querrey Institute for BioNanoTechnology (SQI), Northwestern University, Chicago, IL 60611, USA.
authors.forename: Woon Teck
authors.initials: WT
authors.lastname: Yap
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 300 E Superior St, Chicago, IL 60611, USA. Electronic address: s-d-miller@northwestern.edu.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.affiliation: Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA. Electronic address: ldshea@umich.edu.
authors.forename: Lonnie D
authors.initials: LD
authors.lastname: Shea
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000008:administration & dosage* / Q000737:chemistry; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D010455:Peptides / Q000008:administration & dosage*; D011098:Polyglactin 910 / Q000008:administration & dosage
chemical_list: D006182:H-Y Antigen; D010455:Peptides; D011098:Polyglactin 910
keywords: Bone marrow engraftment; PD-1 costimulation; PLG nanoparticles; Tolerance; Transplantation