title: Activation of invariant Natural Killer T lymphocytes in response to the α-galactosylceramide analogue KRN7000 encapsulated in PLGA-based nanoparticles and microparticles.
abstract: Invariant Natural Killer T (iNKT) cells have potent immunostimulatory activities that could be exploited for human therapies. The high-affinity CD1d antigen α-galactosylceramide analogue KRN7000 (KRN) activates a cascade of anti-tumor effector cells and clinical studies have already had some initial success. To improve the efficacy of the treatment, strategies that aim to vectorize KRN would be valuable. In this study, we intended to characterize and compare the effect of KRN encapsulated in poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs, 90nm) and microparticles instead of macroparticles (MPs, 715nm) on the iNKT cell response. Our data show that whatever the size of the particles, vectorized KRN induced potent primary activation of iNKT cells in vitro and in vivo. We show that endocytosis of PLGA-based particles by dendritic cells is mediated by a clathrin-dependent manner and that this event is important to stimulate iNKT cells. Finally, we report that KRN vectorized in NPs and MPs exhibited different behaviours in vivo in terms of iNKT cell expansion and responsiveness to a recall stimulation. Collectively, our data validate the concept that KRN encapsulated in PLGA-based particles can be used as delivery systems to activate iNKT cells in vitro and in vivo.
authors.affiliation: Institut Pasteur de Lille, Center for Infection and Immunity of Lille, F-59019 Lille, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Macho Fernandez
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.forename: Josette
authors.initials: J
authors.lastname: Fontaine
authors.forename: Emilie
authors.initials: E
authors.lastname: Bialecki
authors.forename: Fabien
authors.initials: F
authors.lastname: Rodriguez
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Werkmeister
authors.forename: Vanessa
authors.initials: V
authors.lastname: Krieger
authors.forename: Christophe
authors.initials: C
authors.lastname: Ehret
authors.forename: Béatrice
authors.initials: B
authors.lastname: Heurtault
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.forename: Benoit
authors.initials: B
authors.lastname: Frisch
authors.forename: Didier
authors.initials: D
authors.lastname: Betbeder
authors.forename: Christelle
authors.initials: C
authors.lastname: Faveeuw
authors.forename: François
authors.initials: F
authors.lastname: Trottein
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002966:Clathrin / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D005699:Galactosylceramides / Q000008:administration & dosage* / Q000276:immunology* / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008863:Microspheres; D053758:Nanoparticles / Q000737:chemistry*; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D055672:Static Electricity; D013499:Surface Properties
chemical_list: D000970:Antineoplastic Agents; D002966:Clathrin; D004337:Drug Carriers; D005699:Galactosylceramides; D007376:Interleukin-2; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D015847:Interleukin-4; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007371:Interferon-gamma; C103873:KRN 7000