The IgE adjuvant effect of particles: characterisation of the primary cellular response in the draining lymph node
Introduction
The prevalence of asthma and allergic diseases appears to have increased in industrialised countries during the last decades (Beasley et al., 2000). Although genetic factors are important in the development of allergic disease, the apparent rapid increase in prevalence is unlikely to have been caused by genetic changes (Nicolai, 1997), and must have been due to environmental changes. Different types of particles have been shown to increase the allergic immune response to allergens, both in humans (reviewed in Nel et al., 1998) and in animal models (reviewed in Granum and Lovik, 2002). Many of these studies dealt with diesel exhaust particles, in accordance with epidemiological studies showing an association between traffic-related pollution and asthma and allergy symptoms or sensitisation (Janssen et al., 2003, Venn et al., 2001, Wyler et al., 2000).
Diesel exhaust is a complex mixture, composed of both a particulate and a gaseous phase. Solid diesel exhaust particles consist of a carbonaceous core with metals and hundreds of substances adsorbed to a large surface area (BeruBe et al., 1999, Cohen and Nikula, 1999). The role of the soluble (chemical) versus the insoluble (physical) part for the adjuvant effect of particles has been a subject of several investigations. Polystyrene and carbon black particles, both models for the insoluble particle core, have been found to exert an adjuvant effect on allergen-specific IgE production in mice (Lovik et al., 1997, Granum et al., 2001a; van Zijverden et al., 2001, Maejima et al., 1997). However, little is known about the mechanisms causing this adjuvant effect of “clean” particles.
The main objective of the present studies was to investigate the cellular mechanisms whereby “clean” particles affect the primary response to the allergen. The primary immune response to an antigen takes place in the draining lymph nodes (Zinkernagel, 2000) and particles have been shown to be carried to the draining lymph nodes (Harmsen et al., 1985, Randolph et al., 1999). Therefore, in a footpad injection model, we studied how PSP, alone or together with the allergen ovalbumin (OVA), affected the cells in the draining popliteal lymph node (PLN). We measured cell numbers and subtypes, cell proliferation, expression of a number of cell surface molecules (MHC class II, CD40, CD80, CD86, CD23, CD69 and CD25) and the production of cytokines (IL-4, IL-10 and IFN-γ) by PLN cells. By comparing the primary cellular response to the Th2-adjuvant PSP with the Th1-adjuvant CpG-DNA, we aimed to determine which cellular events were important for the development of the antibody response augmented by PSP.
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Animals
Female inbred 6–8-week-old normal and nude (nu/nu) BALB/cA mice (Taconic M&B A/S, Ry, Denmark) were housed, five to eight animals per cage, on BeeKay bedding (B&K Universal AS, Nittedal, Norway) in type III macrolon cages in filter cabinets (Scantainers). The mice were exposed to a 12-h/12-h light/dark cycle (30–60 lux in cages), room temperature (20 ± 2 °C) and 40–60% relative humidity. The animals were given pelleted food (RM1, SDS, Essex, UK) and tap water ad libitum. The experiments were
The adjuvant effect of PSP on OVA-specific IgE, IgG1 and IgG2a antibodies
HBSS, OVA, PSP or OVA + PSP were injected on day 0, followed by an injection of OVA on day 21. On day 26, the levels of the Th2-associated OVA-specific IgE and IgG1 antibodies were significantly higher for mice immunised with OVA + PSP compared to mice injected with HBSS, OVA or PSP (Fig. 1, A and B). A similar increase was not observed for the Th1-associated IgG2a levels (Fig. 1C). OVA alone increased the IgG1 levels slightly but significantly.
Kinetics and characterisation of particle-containing cells in the lymph node
After a single injection of fluorescent PSP with
Discussion
We found that the adjuvant effect of polystyrene particles on the IgE response to OVA was associated with an increased early cellular response in the draining popliteal lymph node (PLN), peaking on day 5 after subcutaneous injection into the footpad. This cellular response included increased B and T lymphocyte numbers, as well as increased expression of molecules involved in the B–T lymphocyte interaction, the IgE regulatory molecule CD23 and the activation marker CD69. In addition, we found an
Acknowledgements
We thank Else-Carin Groeng, Åse Eikeset, Berit A. Stensby and Rita-Bente Leikvold for expert technical assistance. Also, we thank Ingrid Melkild and Mari Samuelsen for useful discussions during preparation of the manuscript. This work was supported by the Norwegian Research Council, grant no. 129593/310.
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