Modulation of the 3'IgH Regulatory Region (3'IgH RR), a prospective in vitro screening tool for identifying potential immunotoxicants

by Henseler, Rebecca Anne

The immune system is critical to human survival. However, assessing alterations of immune function by potential immunotoxicants is complicated by the diffuse nature of the immune system, which is composed of various effector cells each with differing effector functions. Current immunotoxicity testing is limited to animal studies. We have developed a model, which may provide an in vitro alternative to animal studies in identifying immunotoxicants that specifically target B cell function (i.e., alteration of immunoglobulin (Ig) or expression and antibody secretion). This model consists of a well-characterized B cell line, CH12.LX, which appears to appropriately model primary B cell function. We have stably transfected the CH12.LX cell line with a transgene regulated by an enhancer, the 3’Ig heavy chain regulatory region (3’IgH RR), purported to control Ig heavy chain gene expression. Our previous work has identified the 3’IgH RR as a sensitive target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) possibly mediated by activation of the aryl hydrocarbon receptor (AhR) signaling pathway. We have tested our model with several structurally diverse chemicals shown to activate the AhR signaling pathway and found an association between AhR activation and inhibition of both 3’IgH RR activation and Ig protein expression. We have also tested two chemicals previously shown to activate humoral immunity through non-AhR receptors. Results indicate that our model appropriately identifies immunomodulators of two receptor-signaling pathways, each leading to altered immunoglobulin expression. (Supported by the Colgate-Palmolive Grants for Alternative Research and the Boonshoft School of Medicine, WSU)