ToxSci Advance Access originally published online on September 18, 2009
Toxicological Sciences 2009 112(2):363-373; doi:10.1093/toxsci/kfp224
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Establishment of an Immunoglobulin M Antibody-Forming Cell Response Model for Characterizing Immunotoxicity in Primary Human B Cells
Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
1 To whom correspondence should be addressed at Department of Pharmacology and Toxicology, Center for Integrative Toxicology, 315 National Food Safety and Toxicology Building, East Lansing, MI 48824-1317. Fax: (517) 432-3218. E-mail: kamins11{at}msu.edu.
Received July 15, 2009; accepted September 11, 2009
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Abstract |
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Rodent models have been extensively utilized to identify putative human immunotoxicants; however, even when immunotoxicity is established, uncertainty remains whether the effects are predictive of human risk. Therefore, the objective of this study was to establish a polyclonal immunoglobulin M (IgM) antibody-forming cell (AFC) response model to directly characterize immunotoxicity in primary mouse or human B cells. CD40 ligand (CD40L) was selected to activate B cells because it effectively drives both primary human and mouse B cells in vitro to AFC in a physiologically relevant manner to mimic T-cell-dependent antibody responses in vivo. In this model, the IgM AFC response is induced by cell surface–expressed CD40L and promoted by recombinant cytokines. Reported here are the conditions required to induce IgM AFC responses using mouse splenic B cells or human peripheral blood B cells, allowing for species comparisons. Moreover, less than one order of magnitude difference was observed in the CD40L-induced B-cell AFC responses based on data from multiple donors. In addition to antibody production, proliferation and phenotypic changes characteristic of B-cell activation as well as the plasma cell phenotype were also significantly induced. Finally, two well-characterized immunotoxicants, arsenic and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, using the CD40L-induced IgM AFC response were compared in both mouse and human B cells. Collectively, an IgM AFC response model is described that can be applied to assess the sensitivity of antibody responses to modulation by xenobiotics using mouse as well as human primary B cells.
Key Words: immunotoxicology; antibody response; human B cell; in vitro model.