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Slow CCL2-dependent translocation of biopersistent particles from muscle to brain.

hal.structure.identifierInstitut Mondor de Recherche Biomédicale [IMRB]
dc.contributor.authorKHAN, Zakir
hal.structure.identifierCHU Pitié-Salpêtrière [AP-HP]
hal.structure.identifierImmunité et Infection
dc.contributor.authorCOMBADIÈRE, Christophe
hal.structure.identifierIMRB - "Biologie du système neuromusculaire" [Créteil] [U955 Inserm - UPEC]
dc.contributor.authorAUTHIER, François-Jérôme
hal.structure.identifierInstitut Mondor de Recherche Biomédicale [IMRB]
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
dc.contributor.authorITIER, Valérie
hal.structure.identifierLaboratoire de Physico-Chimie des Matériaux Luminescents [LPCML]
hal.structure.identifierInstitut Lumière Matière [Villeurbanne] [ILM]
dc.contributor.authorLUX, François
hal.structure.identifierThe Birchall Centre
dc.contributor.authorEXLEY, Christopher
hal.structure.identifierInstitut Mondor de Recherche Biomédicale [IMRB]
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
dc.contributor.authorMAHROUF-YORGOV, Meriem
hal.structure.identifierInstitut Mondor de Recherche Biomédicale [IMRB]
dc.contributor.authorDECROUY, Xavier
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
dc.contributor.authorMORETTO, Philippe
hal.structure.identifierLaboratoire de Physico-Chimie des Matériaux Luminescents [LPCML]
hal.structure.identifierInstitut Lumière Matière [Villeurbanne] [ILM]
dc.contributor.authorTILLEMENT, Olivier
hal.structure.identifierInstitut Mondor de Recherche Biomédicale [IMRB]
hal.structure.identifierService d'Histologie
hal.structure.identifierIMRB - "Biologie du système neuromusculaire" [Créteil] [U955 Inserm - UPEC]
dc.contributor.authorGHERARDI, Romain
hal.structure.identifierInstitut Mondor de Recherche Biomédicale [IMRB]
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
hal.structure.identifierIMRB - "Biologie du système neuromusculaire" [Créteil] [U955 Inserm - UPEC]
dc.contributor.authorCADUSSEAU, Josette
dc.date.issued2013
dc.identifier.issn1741-7015
dc.description.abstractEnBACKGROUND: Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocyte-lineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA). METHODS: On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used. RESULTS: Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation. CONCLUSION: Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production.
dc.language.isoen
dc.publisherBioMed Central
dc.subject.enAlum
dc.subject.enVaccine adverse effect
dc.subject.enVaccine adjuvant
dc.subject.enNanomaterial biodistribution
dc.subject.enNanomaterial neurodelivery
dc.subject.enMacrophages
dc.subject.enMacrophagic myofasciitis
dc.subject.enCCL-2
dc.subject.enSingle nucleotide polymorphisms (SNPs)
dc.title.enSlow CCL2-dependent translocation of biopersistent particles from muscle to brain.
dc.typeArticle de revue
dc.identifier.doi10.1186/1741-7015-11-99
dc.subject.halSciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Génomique, Transcriptomique et Protéomique [q-bio.GN]
dc.description.sponsorshipEuropeEuropean Community's Seventh Framework Programme in the project ENDOSTEM "Activation of vasculature
bordeaux.journalBMC Medicine
bordeaux.page99
bordeaux.volume11
bordeaux.issue1
bordeaux.peerReviewedoui
hal.identifierinserm-00807777
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//inserm-00807777v1
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