Research Grants 1997-1998

A New Approach to Modeling Contact Dermatitis

Phillip S. Magee, PhD
BIOSAR Research Project, Vallejo, California

Sensitization in allergic contact dermatitis (ACD) occurs when a hapten reacts with MHC Class 2 molecules on the surface of the Langerhans cell. This event modifies the site which enables a T2 lympocyte to recognize a normally benign resident as a modified stranger. This initial event is key to the entire subsequent process altering the immune system to later invasions of the hapten. It requires over 20 animals and more than one month to evaluate by the guinea pig maximization test and may or may not be applicable to man.

The major reactive event is clearly kinetic in nature and requires the hapten to access and react with the cell surface molecules during its brief residence in the viable epidermis. Should it bind in the stratum corneum (too reactive) or pass into the dermis as reactive (code = 1) or non-reactive (code = 0) when combined with mechanistic factors describing transport and binding, classify allergens and non-allergens about as well as clinical testing.

Our lab has developed two successful models, one of which is published, and these have been applied through several publications to drugs, pesticides and other models to describe the intensity of ACD (1-4, non, weak, moderate, strong). This has only been partially successful and the problem appears to be our use of dichotomous substructure descriptors which have only 0 and 1 values.

Recently, I discovered that quinone haptens could be modeled relatively by simulating the protein-hapten reaction with simple nucleophiles (MeO-, MeS-). The reactants and first intermediate (adduct) were modeled by the semi-empirical program, AM1. The heat of reaction is derived from the difference between computed reactant and product heats of formation. The values are large and well-spread, allowing a simple ranking of each quinone in reactivity by the exotherm of the model reaciton. In addition, I was able to generate correlations with electronic sigma values that permit the prediction of structures beyond the study set. This work was presented last summer at the Gordon Conference on QSAR.

There are approximately 40-50 different hapten substructures (ACD Alerts) that react with protein nucleophiles to form anionic intermediates. I propose to study each case by the same technique applied to the quinones with the purpose of developing a graded reactivity scale for each hapten structure. These relative values will represent a major step in converting qualitative concepts of haptenization into descriptors suitable for the study and prediction of graded responses.

Although some models have appeared in the literature in addition to our own, all are currently incapable of a graded response and animal testing remains the standard. The success of this proposal will not eliminate the animal test, but should go far in minimizing its routine use for non-commercial products.