title: Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model.
abstract: Leishmania (Viannia) panamensis (L. (V.) panamensis) is a species of protozoan parasites that causes New World leishmaniasis, which is characterized by a hyper-inflammatory response. Current treatment strategies, mainly chemotherapeutic, are suboptimal due to adverse effects, long treatment regimens, and increasing drug resistance. Recently, immunotherapeutic approaches have shown promise in preclinical studies of leishmaniasis. As NPs may enable broad cellular immunomodulation through internalization in phagocytic and antigen-presenting cells, we tested the therapeutic efficacy of biodegradable NPs encapsulating a pathogen-associated molecular pattern (PAMP), CpG-rich oligonucleotide (CpG; NP-CpG), in mice infected with L. (V.) panamensis. NP-CpG treatment reduced lesion size and parasite burden, while neither free CpG nor empty NP showed therapeutic effects. NP-encapsulation led to CpG persistence at the site of infection along with an unexpected preferential cellular uptake by myeloid derived suppressor cells (MDSCs; CD11b(+)Ly6G(+)Ly6C(-)) as well as CD19(+) dendritic cells. This corresponded with the suppression of the ongoing immune response measured by the reduction of pathogenic cytokines IL-10 and IL-13, as well as IL-17 and IFNγ, in comparison to other treatment groups. As chronic inflammation is generally associated with the accumulation of MDSCs, this study may enable the rational design of cost-effective, safe, and scalable delivery systems for the treatment of inflammation-mediated diseases.
authors.affiliation: Yale School of Engineering and Applied Science, USA.
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Siefert
authors.affiliation: Yale School of Public Health, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Ehrlich
authors.affiliation: Yale Medical School, Department of Immunobiology, New Haven, CT, USA.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Corral
authors.affiliation: Yale School of Public Health, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.affiliation: Yale School of Public Health, USA. Electronic address: diane.mcmahon-pratt@yale.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
authors.affiliation: Yale School of Engineering and Applied Science, USA; Department of Animal Health, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology*; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000737:chemistry; D007891:Leishmania; D007896:Leishmaniasis / Q000276:immunology* / Q000469:parasitology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D003692:Delayed-Action Preparations; D007155:Immunologic Factors
keywords: CpG; Immunotherapy; Leishmaniasis; Nanoparticles; PAMP; Parasite