The LLNA: A Brief Review of Recent Advances and Limitations

Abstract

Allergic contact dermatitis is the second most commonly reported occupational illness, accounting for 10% to 15% of all occupational diseases. This highlights the importance of developing rapid and sensitive methods for hazard identification of chemical sensitizers. The murine local lymph node assay (LLNA) was developed and validated for the identification of low molecular weight sensitizing chemicals. It provides several benefits over other tests for sensitization because it provides a quantitative endpoint, dose-responsive data, and allows for prediction of potency. However, there are also several concerns with this assay including: levels of false positive responses, variability due to vehicle, and predictivity. This report serves as a concise review which briefly summarizes the progress, advances and limitations of the assay over the last decade.

LLNA variability: An essential ingredient for a comprehensive assessment of non-animal skin sensitization test methods and strategies

“…Another crucial factor affecting the variability is the choice of the vehicle. Vehicle impact has already been explored in some detail, for example by Jowsey et al (2008), who reported a tendency toward underestimated potency for aqueous vehicles or propylene glycol, and has been briefly reviewed (Anderson et al, 2011). Our analysis supports the general view that repeat testing with different vehicles leads to more variable EC3 values than repeat testing with the same vehicle.…”

Route-dependent systemic and local immune effects following exposure to solutions prepared from titanium dioxide nanoparticles

“…It is well established that non-sensitizing irritants can induce proliferation in the LLNA, thereby confounding the ability to distinguish between irritants and sensitizers. However, responses that exceed a stimulation index (SI) of 3-fold over control are typically associated with sensitizers and not irritants (Anderson et al, 2011), although exceeding an SI of 3 does not confirm that a chemical is truly a sensitizer. Although hypersensitivity to implanted titanium has been documented in humans (Müller & Valentine-Thon, 2006) and is consistent with a possible systemic hypersensitivity response to nano-TiO 2 in the present study, further study is warranted to more clearly delineate the irritant vs systemic hypersensitivity of nano-TiO 2 following parenteral administration.…”

A Perspective on the Challenges and Issues in Developing Biomarkers for Human Allergic Risk Assessments

“…Currently preclinical allergic risk assessments rely on animal-based tests [18]. However, this approach has been criticized for providing poor clinical relevance due to species variation in immune responses and drug metabolism [19][20][21].…”