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

BMC Medicine

Josette Cadusseau⁷  Romain K Gherardi¹  Olivier Tillement⁴  Philippe Moretto³  Xavier Decrouy⁷  Meriem Mahrouf-Yorgov⁵  Christopher Exley²  François Lux⁴  Valérie Itier⁷  François-Jérôme Authier¹  Christophe Combadière⁶  Zakir Khan⁷ 

[1] AP-HP, Hôpital H. Mondor - A. Chenevier, Service d’Histologie, Centre de Référence Neuromusculaire GNMH, 51 Avenue du Maréchal de Lattre de Tassigny, Créteil, 94000, France;The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, UK;CNRS UMR 5797, Centre d'Etudes Nucléaires de Bordeaux Gradignan, Allée du haut Vignaud, Gradignan, 33175, France;Université Claude Bernard Lyon 1, 2 rue Victor Grignard, Villeurbanne, 69622, France;Faculté des Sciences et Technologie, UPEC, 61 Avenue du Général de Gaulle, Créteil, France;AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service d’Immunologie, 11 Boulevard de l’Hôpital, Paris, 75013, France;Université Paris Est, Faculté de Médecine, 8 rue du Général Sarrail, Créteil, 94010, France

关键词: Single nucleotide polymorphisms (SNPs);    CCL-2;    Macrophagic myofasciitis;    Macrophages;    Nanomaterial neurodelivery;    Nanomaterial biodistribution;    Vaccine adjuvant;    Vaccine adverse effect;    Alum;   

Others  :  857104
DOI  :  10.1186/1741-7015-11-99

 received in 2012-11-12, accepted in 2013-03-07,  发布年份 2013

【 摘 要 】

Background

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.

【 授权许可】

   
2013 Khan et al.; licensee BioMed Central Ltd.

【 图 表 】

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