The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

Research Grants 2005-2006

An in vitro model system to evaluate drug effects on B-lymphocyte survival and antibody production

Donna Muscarella, PhD
Cornell University College of Veterinary Medicine

The immune system is among the most sensitive of body systems to disruption by immunotoxic drugs and environmental pollutants. Testing chemicals in animals has identified some immunotoxic chemicals, but such tests are animal-use intensive, costly, and generally lack sensitivity. Furthermore, animal tests seldom reveal which cellular components and biochemical pathways are disrupted by immunotoxic agents. Consequently, there is the need to develop alternative in vitro systems that can provide the necessary mechanistic information that can enable investigators to better predict drug and chemical effects on immmune system function. One fundamental immune system activity that is a potentially important target of immunotoxic agents is the positive selection of specific clonal populations of B-lymphocytes (BLs) that ultimately generate the diverse repertoire of antibodies needed to recognize foreign antigens. This process takes place within the germinal centers of lymph nodes, where the interaction of BLs with specialized, follicular dendritic cells activates specific biochemical pathways that ultimately control BL survival and antibody production. However, these cellular interactions and biochemical pathways are susceptible to interference by exogenous drugs and chemicals. In this project a co-culture system of human BL-cell lines in contact with the HK-follicular dendritic cell line will be used to model the process of positive selection that occurs in germinal centers of lymph nodes. This in vitro germinal center model will be used to identify specific molecular targets and signaling pathways that are inhibited or activated by particular chemicals, ultimately causing disruption of productive interactions between BLs and HK cells. Candidate immunotoxic agents will be studied including environmental pollutants, anti-cancer drugs, and anti-inflammatory drugs. The specific pathway altered by these agents will be established and the information will be used to generate predictive models for potential immunotoxic effects of different classes of chemicals.