Avon Program Project Explores Allergic Contact DermatitisBy Deborah Rudacille If guinea pigs are less often used as surrogates for human beings in dermatological testing today, credit for the advance is due in large part to Avon Products, Inc., which has contributed over $1 million since 1988 to a collaborative research project on allergic contact dermatitis (ACD) funded through the Johns Hopkins Center for Alternatives to Animal Testing. The small domesticated rodent, whose name has become a synonym for "research subject," is gradually being replaced by a battery of scientifically sophisticated in vitro tests, many of them developed from basic research carried out by the Avon-funded investigators. "The project we were working on, using Interleukin-1 [an immune system activator] as a marker for sensitizers, has become standard in the pharmaceutical industry," said Fredika Robertson, Ph.D., associate professor of medical microbiology and immunology, Ohio State University College of Medicine. Funded by Avon and CAAT for four years, Robertson began a fruitful collaboration with fellow grantee Daniel M. Sauder, M.D., chief of the Division of Dermatology, University of Toronto, as a result of their interaction at the twice-yearly seminars held at CAAT as part of the Avon program project. CAAT developed this approach to working with industry, providing specific methodological approaches to address pressing toxicological issues, in 1988. Program project meetings are typically composed of three academic investigators funded by Avon, the company's manager of toxicology and staff from its toxicology division, CAAT staff and Hopkins faculty whose research relates to the topic. Robertson believes that these meetings amplified the impact of the individual scientists' investigations and greatly enhanced the value of the research. That perception is shared by nearly everyone associated with the project. "You can have the same kinds of presentations at bigger meetings, but you don't have the intimacy and the give and take that you have in the smaller program project meetings," said Anthony Gaspari, M.D. assistant professor, dermatology, University of Rochester Medical Center. Noting that the quality of the group interaction facilitated a higher degree of trust and sharing than is possible at the average scientific conference, Fredika Robertson said that, "there is no question that the inter-collegial cooperation was very helpful." She added that "when you get a group of people working in one area getting together, sharing results, it also makes you more competitive--and that's a good thing." "The project has been quite successful at bringing together individuals who were working independently and getting them to work together in a collaborative manner," said Kevin J. Renskers, Ph.D., manager of toxicology at Avon and the company's liasion to CAAT since 1990. "The quality of the science done by these investigators has been outstanding--innovative and unique research on the basic mechanisms of delayed contact hypersensitivity. As a result, they have truly moved the science forward." Initially conceived and implemented in 1988 as a three-year, $300,000 grant from Avon Products, Inc. to identify promising alternative approaches to allergy tests, the Avon Program Project gradually evolved into a tightly-focused investigation of the cascade of molecular events which create an allergic reaction when a substance is applied to human skin. Skin allergy testing is necessary for a wide variety of products, including cosmetics, pharmaceuticals, food additives, household products and industrial chemicals. In the United States, approximately 40% of all work-related medical disorders involve the skin. A high percentage of these skin disorders are caused by allergic contact dermatitis. Avon's contract with CAAT has been renewed three times, with the current program project scheduled to run until March 1997. Eight academic groups have been funded thus far. Their research has explored both the nature of the chemicals prone to initiating allergic responses in susceptible individuals and the role that various types of skin cells play in allergic response. Howard Maibach, M.D., Department of Dermatology, University of California, San Francisco, was funded to investigative the potential of QSAR (quantitative structure-activity relationships) to predict the allergic potential of chemicals. QSAR consists of the creation of large computer databases of chemicals and their properties. This data is then correlated with various biological endpoints, including the chemical's ability to cause cancer, birth defects and other disease. This technology was adapted by Maibach and his co-workers to predict which of 22 structural characteristics of a group of chemicals might be associated with allergic response. Nine of the structural characteristics proved to be associated with the phenomenon. When the information was plugged into a complex formula in which each feature was weighted according to its significance, Maibach's QSAR model was able to predict a chemical's potential for contact allergy with 80-90% accuracy. "The total funding, although small, led to an international dialogue, by telephone, fax, e-mail and personal and open meetings that clearly spurred international interest in QSAR of ACD," said Maibach. The small size of the grants ($20,000 initially, $30,000 today) and the fact that investigators need to re-apply each year are perceived as limiting factors by all of the investigators interviewed. "There's not a tremendous amount that you can do with that sum of money," said Anthony Gaspari. "It helps, but it would have a greater impact if the grants were larger and were awarded in two-to-three year blocks." "Avon is getting quite a lot of bang for its buck," said Fredika Robertson. "One of my colleagues used to project what it actually cost to do the work... We worked harder for that money than for almost anything else." Kevin Renskers responded to the investigators' comments by acknowledging that "yes, the funds are insufficient to do a full-blown research project. But then again, CAAT grants have never been intended to support full research projects. I fully appreciate the invesigators comments and concerns. However, the original philosophy of the program project, which is really a CAAT philosophy and approach, is that the purpose of these grants is to provide seed money for preliminary research, to enable the investigators to develop sufficient data to apply to the larger granting agencies. The bottom line is that they are doing what they're interested in and figuring out a way to do it. That's to their credit." Renskers advises any companies considering launching such a project in an area of interest to "DO IT! It's well worth the investment. Again, the underlying premise is the opportunity to bring together people who may have very diverse approaches to a common question." For the investigators themselves, one of the primary benefits of the program has been the opportunity to work with Renskers and other toxicologists and individuals from industry, "addressing issues that a researcher in dermatology and immunology like me isn't usually exposed to. It's been a real eye-opener and a learning experience," said Gaspari. "Intellectually, it's an interesting issue," said Craig Elmets, professor of dermatology and director, Skin Diseases Research Center, Case Western Reserve University. "The Avon money has enabled me to work on a very important issue with respect to public health. It gave me the opportunity to interface with industry on a project with a mutual goal. Good research is being done here and that has important spin-offs." Both Elmets and Gaspari believe that the Avon-funded research is beginning to have an impact beyond the small circle of investigators and the company involved. "A lot of the investigators have stayed in the field because of the Avon project. They're presenting their findings at meetings of the Society for Investigative Dermatology and other big meetings. The impact of the research is far-reaching." Despite the limited funds, all of the investigators were grateful for Avon's support. "The grants have allowed my lab to maintain a focus on an important clinical area. In the present funding atmosphere, that becomes even more important," said Gaspari. Avon Program Project Investigators and Projects- Craig Elmets (current) - Cytokine Gene Expression and Allergic Contact Dermatitis
- Anthony Gaspari (current) - Epidermal Cell Expression of Co-Stimulatory Activity in the Induction of Allergic Contact Dermatitis
- Richard Kalish - In Vitro Model of Human Allergic Contact Dermatitis
- Howard Maibach - Development of a QSAR Database for Skin Contact Allergens
- Raj Mitra - Role of Keratinocytes in Cutaneous Inflammation/Immunity
- Fredika Robertson - In Vitro Models for Contact Allergy
- Daniel M. Sauder - Molecular Characterization of Epidermal Cytokines: A Potential In Vitro Assay for Contact Dermatitis
- Wayne Streilein (current) - In Vitro Assay for Hapten-Specific Priming of Human T-Lymphocytes
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