Gene profiling sheds light on skin sensitization

International report - Gene and protein expression profiling is providing new and exciting insights into the mechanisms involved in the acquisition of skin sensitization and the development of allergic contact dermatitis.

These same experimental approaches also support the search for novel biomarkers that can be exploited in the development of new approaches to the identification and characterization of skin sensitizing chemicals.

The search is on

Dr. Kimber notes that, "Of pivotal importance are epidermal Langerhans cells (LC) that have responsibility for the recognition, internalization, processing and subsequent presentation to the immune system of antigens (including chemical allergens) encountered at skin surfaces."

Following topical exposure to skin sensitizing chemicals, LC (including allergen-bearing LC) are mobilized and induced to migrate from the skin to regional lymph nodes. While en route to lymph nodes, LC are subject to a functional maturation whereby they gain immunostimulatory properties that allow them to present antigen effectively to responsive T lymphocytes. As a result, allergen-specific T lymphocytes become activated and are induced to divide and differentiate, which is the central event in the acquisition of skin sensitization.

Although understanding of LC biology and the events associated with the development of skin sensitization have increased significantly during the last decade, the exact molecular mechanisms involved remain unclear. For this reason, Dr. Kimber and colleagues within Syngenta and elsewhere are using a variety of techniques to map out changes in gene expression and protein production stimulated following dermal exposure to a contact allergen, and during the development of skin sensitization.

Paving the way for future advances

"In particular, modern microarray technology allows us to monitor simultaneously changes in the expression of many thousands of genes that are associated with the initiation of responses to skin sensitizing chemicals. These investigations are providing us with new insights into the way in which skin sensitization develops and into the important cellular-molecular interactions, but in the future may also allow discrimination between different kinds of chemical stimuli in the skin," Dr. Kimber notes.

At a more practical level, the hope is that an improved understanding of the immunobiology of skin sensitization, and the identification of robust biomarkers, will allow the design and development of new and improved approaches to the toxicological evaluation of skin sensitization hazards, including the future use of methods that do not require the use of animals.

Investigators are using several experimental approaches to develop these gene expression profiles. Using laboratory animals, they are examining changes in gene expression in the skin of mice exposed to contact allergens. Secondly, they are using human keratinocytes and LC-like cells to evaluate responses of these cell types to contact allergens. Research using these models is ongoing, as investigators begin to narrow down the pool of molecules likely to be involved in these immunologic processes.

Close to pay dirt?

Dr. Kimber notes that his group has isolated a small number of candidate proteins that seem to be uniquely associated with the development of skin sensitization.

"This might provide us with the opportunity to distinguish between contact allergenicity and skin irritancy, and contact allergenicity and sensitization to other types of chemical allergens."

Disclosure: Dr. Kimber is an employee of Sygenta Central Toxicology Laboratory.