An integrated model for the differentiation of chemical-induced allergic and irritant skin reactions.

Contact and photocontact allergic as well as irritant and photoirritant skin reactions represent a major problem in clinical dermatology and during the development of new pharmaceuticals. Furthermore, there is a lack of in vitro and in vivo assays that provide a clear differentiation between allergic and irritant skin reactions. Here, we describe an integrated model to differentiate between chemical-induced allergic and irritant skin reactions by measuring objective and easy-to-determine parameters within both skin and skin-draining lymph nodes. Dose-response studies with standard contact and photocontact allergens as well as irritants and photoirritants revealed that irritants predominantly induced skin inflammation, which in turn stimulated draining lymph node cell proliferation. In contrast, the induction phase of contact or photocontact allergy was characterized by marginal skin inflammation, but a marked activation and proliferation of skin-draining lymph node cells. Therefore, a differentiation index (DI) was defined describing the relation between skin-draining lymph node cell activation (lymph node cell count index) and skin inflammation (ear swelling). A DI > 1 indicates an allergic reaction pattern whereas DI < 1 demonstrates an irritant potential of a chemical. Experiments with the contact allergen oxazolone, the photocontact allergen TCSA + UVA, the irritant croton oil, and the photoirritant 8-methoxypsoralen + UVA confirmed the predictive value of DI. Furthermore, flow cytometric analysis of lymph node-derived T- and B-cell subpopulations revealed that contact sensitizer, but not irritant, induced the expression of CD69 on the surface of I-A+ cells. In conclusion, further studies with a broad range of irritants and allergens will be required to confirm general applicability.