Microsphere translocation and immunopotentiation in systemic tissues following intranasal administration
Introduction
Investigations of intranasal (i.n.) immunisation have shown that antigen microencapsulation, or antigen adsorption onto microparticulates, confers a significant adjuvant effect [1], [2]. The exact reason for this immunopotentiating effect is not certain, and the extent to which microparticulates are absorbed across epithelial barriers in the respiratory tract is largely undelineated. It is feasible that M-cells in the nasopharyngeal duct, tonsils and bronchus associated lymphoid tissue (BALT) [3], [4], [5] may facilitate particle uptake across epithelial barriers at these locations. There is also good evidence to indicate that, following transepithelial absorption, microparticle translocation to local immunoresponsive tissues may occur following intranasal delivery [6]. This is strongly supported by the work of Carr et al. [7] and Ridley Lathers et al. [8]. These authors demonstrated the uptake of 1.0 μm fluorescent polystyrene latex and 1.7 μm poly(lactide-co-glycolide) microspheres into rodent nasal associated lymphoid tissues (NALT) and draining cervical lymph nodes after intranasal administration. Prior to these investigations, we demonstrated that nasally delivered 1.0 μm latex microspheres could rapidly enter the blood circulation of experimental animals [9]. To expand these data, we have investigated microparticle uptake and trafficking to systemic compartments of immunological significance, such as thoracic lymph nodes and spleen, following intranasal (i.n.) delivery. Concomitantly the kinetics of the immune response to a microencapsulated recombinant antigen, which is currently undergoing clinical evaluation as an improved vaccine for plague, after i.n. administration, was studied.
Section snippets
Animals
Experimentation strictly adhered to the 1986 Scientific Procedures Act. Female BALB/c mice (25 g, 6-week-old) were used for in vivo studies. Mice were lightly anaesthetised with an inhaled gaseous mixture of 3% (v/v) halothane (RMB Animal Health Ltd., UK) in oxygen (300 cm3 min−1) and nitrous oxide (100 cm3 min−1) for i.n. dosing procedures. Histology and a modification of a method described by Ebel [10] using fluorescence-activated cell sorting (FACS), were used to investigate the in vivo
Histological analysis following intranasal administration of FITC labelled microspheres
We observed a different pattern of particle uptake and distribution in mice nasally dosed with microspheres suspended in 10 and 50 μl volumes of PBS. Also, the tissular distribution of microspheres differed over the 10 day period. Irrespective of administration vehicle volume, many fluorescent particles were observed within excised NALT from 15 min of administration. Mice treated with 10 μl volumes of Fluoresbrite™ spheres showed little evidence of particle translocation to liver and spleen,
Discussion
The histological and cell sorting data gleaned in these experiments corroborate the observations of others [6], [7], [8] that a small percentage of nasally applied microspheres may be translocated into mucosal associated lymphoid tissues and draining lymph nodes. However, here we have identified that microspheres can also access sites that would be expected to result in the induction of systemic immunological responses (spleen). In our model, a prerequisite for significant particle transference
Acknowledgements
We gratefully acknowledge the contribution of Roger Bird (FACS analysis), Derek Stirling, Dr Alan Perris and Dr I.D. Spiers.
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