Abstract
Calcineurin inhibitors potentially prevent pro-allergic mediator release from basophils and mast cells but are rarely used systemically due to ubiquitous expressions of target signaling proteins. However, specific targeting of allergic effector cells with these inhibitors could circumvent unwanted side effects. We recently demonstrated the biocompatibility of gold nanoparticles (AuNPs) as a platform for non-toxic delivery of signaling inhibitors due to unique physicochemical properties of these nanomaterials. Since AuNPs can be conjugated with both anti-allergic drugs and antibodies or other proteins that specifically recognize basophils and mast cells, our aims were to assess specific targeting of allergic effector cell function using AuNPs conjugated with the calcineurin inhibitor ascomycin. Purified human basophils and LAD2 human mast cells were used for investigations with AuNPs conjugated either to CD203c antibodies or containing stem cell factor (SCF), respectively, which were amine-coupled to acidic groups of reduced glutathione (GSH). GSH was also used as a spacer for immobilization of ascomycin on the gold surface. AuNPs conjugated with anti-CD203c and ascomycin strikingly blocked IgE-dependent degranulation of both purified basophils and those present in mixed leukocyte preparations, suggesting specific targeting of these cells. In contrast, LAD2 mast cell responses were not inhibited using anti-CD203c-containing nanoconjugates but were when the conjugates contained SCF. Successful targeting of allergic effector cells using gold nanoconjugates indicates that this technology may have therapeutic potential for the treatment of allergies by specifically delivering highly effective signaling inhibitors with reduced side effects.
Highlights
Inflammatory mediator release, from basophils and mast cells plays a major role in contributing to the symptoms of allergic reactions and these cells may support the underlying tendency for an individual’s immune system to respond in a pro-allergic manner
We compared the effects of NCJs and ascomycin alone on histamine release from purified human basophils stimulated either with anti-IgE (Figures 2A,B and Supplementary Figures 1A,B) or the N-formylated tripeptide fMLP (Figure 2C and Supplementary Figures 1C,D)
In agreement with our previous observations (Gibbs et al, 2014) NCJs containing ascomycin and anti-CD203c substantially inhibited IgEdependent basophil histamine release and this level of inhibition was similar to that seen with 100 nM ascomycin alone
Summary
Inflammatory mediator release, (e.g., histamine) from basophils and mast cells plays a major role in contributing to the symptoms of allergic reactions and these cells may support the underlying tendency for an individual’s immune system to respond in a pro-allergic manner (reviewed in Varricchi et al, 2018). Several pharmacological inhibitors of intracellular signaling, (e.g., Syk and calcineurin inhibitors) have been shown to substantially reduce the ability of mast cells and basophils to release allergic mediators following stimulation of the highaffinity IgE receptor (FcεRI) (Oliver et al, 1994; Zuberbier et al, 2001; Plath et al, 2003; Matsubara et al, 2006; Rossi et al, 2006; Harrison et al, 2007). It is desirable to be able to target effector cells involved in human allergy with drugs that are known to prevent allergen-induced cell activation and the release of pro-inflammatory mediators. We recently reported the proof-of-principle that gold nanoparticles (AuNPs) could be used to target basophils and other cell types with certain signal transduction inhibitors (Gibbs et al, 2014; Yasinska et al, 2018). We observed that AuNPs display inherent antiinflammatory properties themselves by neutralizing the effects of IL-1β (Sumbayev et al, 2013), a cytokine that contributes to allergic inflammation, in asthma
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