In vitro assessment of sensitizing activity of low molecular weight compounds.
Predictive tests to identify the sensitizing properties of chemicals are carried out using animals. There is as yet, no accepted in vitro method for the identification of skin sensitizing chemicals. Such in vitro tests should encompass (parts of) the sensitization phase of contact hypersensitivity. Two cell types are predominantly involved in this process, keratinocytes (KC) and Langerhans cells, the latter being a specialized type of skin dendritic cells (DC). Low molecular weight chemicals act as haptens; KC respond to allergen contact by, among others, producing proinflammatory cytokines, while DC take up the haptenized protein, migrate, and present antigen to T-cells. During migration, DC mature, resulting in a loss of antigen uptake capacity, thereby increasing expression of certain surface molecules. Thus, both cytokine production by KC and surface marker expression by DC may be used as in vitro models for the identification of sensitizers. Several reports have shown that intracellular IL-1 alpha is a promising candidate to identify sensitizers using KC. We have recently shown that the potency of sensitizers may be determined by dose-response analysis of intracellular IL-1 alpha and IL-18 using a murine KC cell line. The ranking of potency using this in vitro method was similar to the ranking previously established using the local lymph node assay. Using DC, effects on the expression of various cell surface markers, cytokines, and molecules involved in antigen uptake have been shown to identify sensitizers. One study showed that also the potency of sensitizers may be determined using DC. Additional studies are required to establish whether KC or DC, or combinations thereof, are most suitable for in vitro identification and potency assessment of sensitizers.
Laboratory for Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands. r.vandebriel@rivm.nl
Rob J
RJ
Vandebriel
François M M
FM
Van Och
Henk
H
van Loveren
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D018675:Toxicity Tests
D007375:Interleukin-1; D020382:Interleukin-18