Animal models for nickel allergy

To the Editor

Vemula et al. report that calcium carbonate and calcium phosphate nanoparticles that are about 70 nm in diameter can capture nickel ions (Ni²⁺) from the surface of the skin¹. They suggest that applying the nanoparticles to the skin may limit the exposure to — and thereby prevent allergy towards — Ni²⁺, which can cause skin irritation and inflammation or contact dermatitis. Although many individuals who are sensitive to Ni²⁺ will benefit from this innovative approach, the animal model used to study the clinical effectiveness of the nanoparticles is problematic.

We have recently shown that the development of nickel allergy requires both an antigen-specific signal that activates T lymphocytes, and a non-specific pro-inflammatory signal that triggers innate immunity². Ni²⁺ induces allergy by interacting with the histidine residues at positions 456 and 458 on the innate immune receptor, Toll-like receptor 4 (TLR4). Because these histidines are present in primates but not in mice, only animals that express the human homologue of TLR4 will develop contact dermatitis, whereas animals that express mouse TLR4 will not². However, it is possible to trigger Ni²⁺ allergy in animals that express mouse TLR4 by coincident application of lipopolysaccharide (LPS) — a classic agonist of TLR4 (ref. 3).

Vemula et al. intended to study nickel allergy in C3H/HeJ mice¹, but this strain contains a mutation at position 712 of the TLR4 that causes the mice to be non-responsive to LPS. This means that because the LPS–TLR4 signalling in the mice is defective, coincident application of LPS will not trigger Ni²⁺ allergy⁴. Furthermore, the experimental design did not include an essential control group — mice that were treated with Ni²⁺ but had not undergone the sensitization procedure. Such a control would allow the discrimination of a genuine hypersensitivity response, which requires the generation of hapten-specific T cells during the sensitization phase, from an irritant toxic effect of Ni²⁺, which does not rely on the generation of Ni²⁺-specific T cells. Therefore, it seems that Vemula et al. have investigated the effect of nanoparticles on Ni²⁺ toxicity, which occurs by events that are independent of TLR4 (ref. 5), rather than investigating Ni²⁺ allergy.

In conclusion, adequate allergy models should be used to clarify whether nanoparticles indeed qualify as the desired preventive tool against contact allergy to Ni²⁺.