A recent report in Nature Medicine describes a new form of allergen-specific immunotherapy for allergy to cats, through targeting the inhibitory receptor FcγRIIb. This approach could be broadly applied for the treatment of any allergy to a defined antigen, and the authors suggest that it might be particularly useful for treating severe food reactions, such as peanut allergy, for which desensitization by repeated injection of small quantities of allergen has been unsuccessful.

One of the main mechanisms of allergy is the release of mediators such as histamine from mast cells and basophils, which results from crosslinking of the surface receptor FcεRI by allergen-specific IgE bound to multivalent allergen. Previous studies have shown that FcεRI signalling leading to mediator release can be inhibited by signalling through FcγRIIb, which binds the constant portion of IgG (Fcγ). Andrew Saxon and colleagues have focused this inhibitory interaction on a specific allergen by creating a chimeric fusion protein (known as GFD) that consists of human Fcγ plus the cat allergen Fel d1. GFD contains the Fcγ binding site for FcγRIIb and also binds Fel d1-specific IgE from the sera of humans who are allergic to cats. In the presence of Fel d1-specific IgE, GFD crosslinks FcγRIIb with FcεRI-bound IgE and should therefore inhibit mediator release in response to the cat allergen.

In vitro, the addition of GFD to cultures of basophils purified from cat-allergic humans (cells which have Fel d1-specific IgE at their surface) inhibited subsequent histamine release in response to Fel d1 in a dose-dependent manner. Similarly, GFD inhibited degranulation of cat-allergen-sensitized cord-blood-derived mast cells. GFD is not an allergen itself, as pre-incubation with GFD did not lead to mediator release from basophils before Fel d1 was added to the culture.

To confirm these results in vivo, transgenic mice expressing human FcεRIα were primed intradermally with human serum containing Fel d1-specific IgE, and skin reactivity at sites of GFD injection was measured after intravenous challenge with Fel d1. As the mast cells of these transgenic mice also express mouse FcγRIIb, which can bind human Fcγ, GFD blocked the skin reaction to Fel d1. GFD did not inhibit the specific IgE-induced response to a control antigen, indicating the allergen specificity of this approach. In an active-sensitization protocol, BALB/c mice were sensitized with Fel d1 and treated with GFD or a control; treatment with GFD inhibited the systemic allergic response to challenge with Fel d1, as indicated by a drop in core body temperature.

Therefore, GFD was shown to inhibit allergen-driven, IgE-mediated mediator release both in vitro and in vivo in an allergen-specific and dose-dependent manner, without itself causing mediator release. This is in contrast to desensitization protocols that use native allergen, which can trigger an allergic reaction, showing the potential of this technique as a new form of antigen-specific immunotherapy.