Nanoparticle-caged antigens could treat allergen-sensitized host

The challenge with immune system-[driven] disorders is the fact that ordinarily such conditions are detected at the later stages when immune system had already developed self-perpetuating "memory circuit". Even now we know very little how to break such "memory circuit".

New study in PNAS suggested an experimental model that were able to tolerize already-sensitized host against allergen. The authors showed that biodegradable nanoparticles incorporating caged antigen, but not simple conjugates, could deliver both prophylactic and therapeutic treatment to allergen-prone host.

For this study the authors have used widely-accepted experimental sensitization protocol in mice to induce T_H2-driven allergy to ovalbumin  antigen (OVA). Next, they proceeded to test three different combination of  nanoparticles + ovalbumin: (1) OVA conjugated to polystyrene nanoparticles (Ag-PS), (2) OVA conjugated to biodegradable poly(lactide-co-glycolide) nanoparticles (Ag-PLG) and (3) OVA caged within biodegradable poly(lactide-co-glycolide) nanoparticles [PLG(Ag)].

First, the authors found that all three nanoparticle combinations displayed potent prophylactic action against allergen when delivered before allergen sensitization (Ag-PLG is shown here).

However, when applied to already allergen-sensitized host, polystyrene nanoparticles induced severe allergic reaction. In contrast, application of Ag-PLG nanoparticles did not induce allergic response in sensitized hosts and even reduced T_H2 cytokines. However, Ag-PLG nanoparticles could not inhibit lung eosinophilia.

Finally, the authors showed that application of PLG nanoparticles with caged OVA antigen could both prophylactically and therapeutically inhibit T_H2-driven allergic response.

In summary, this study showed that nanoparticles incorporating antigens (Ag caging) avoids detection by allergen-specific immune effector molecules (IgE) and instead drives tolerance to allergen.      

David Usharauli

Two distinct, mutually exclusive immune signatures, TH2 and TH17, determine therapy responsiveness in asthma

Asthma is a chronic condition manifested in episodes of airway hypersensitivity (inflammation, smooth muscle constriction) to innocuous signals that ordinarily would cause no tissue response in average individual. Eventually this chronic state leads to tissue remodeling and reduction of oxygen-rich air available for lung. 

Classical, allergic asthma episodes are driven by type 2 (TH2) immune response dominated by IL-4 and IL-13. However, more recently another category of asthma characterized by TH17 signature has been described. It appears that TH17 signature asthma may be more resistant to current asthma therapy.

The new study in Science Translational Medicine provided additional support for asthma stratification based on immune signature. This Genentech study showed that asthma immune profile can be stratified into mutually exclusive, non-overlapping TH2^high and TH17^high signatures.

This is a short paper. Basically, the authors analyzed airway gene signature from 51 asthma patients. They found that asthma patients' immune signature fall in 2 categories: either TH2^high or TH17^high. There is additional double negative category but its immune signature is not known.

Interestingly, both TH2^high and TH17^high signatures were associated with eosinophil infiltration.

Since current asthma therapies mainly target TH2 signature, the authors tested the outcome of α-IL-4/IL-13 blockade on animal asthma model (house dust mite antigen sensitization). As expected, dual blockade of TH2 cytokines significantly reduced airway inflammation.

However, TH2 cytokine blockade also induced TH17 signature, as would have been expected from in vitro studies (though it is not entirely clear from the data if this shift to TH17 pathway induced any clinically-relevant airway inflammation here).

Finally, the authors showed that blockade of both TH2 and TH17 pathways may be necessary to avoid inverse increase in TH2-driven airway hypersensitivity during anti-IL-17 therapy.

In summary, this study suggests that clinical trial design for α-IL-17 target therapy in asthma patients may need modification based on this findings. For example, α-IL-17 therapy alone may be not sufficient or that eosinophil signature could not be used as a exclusion factor for α-IL-17 therapy.

David Usharauli