title: Establishment of an immunoglobulin m antibody-forming cell response model for characterizing immunotoxicity in primary human B cells.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Haitian
authors.initials: H
authors.lastname: Lu
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.forename: Colin M
authors.initials: CM
authors.lastname: North
authors.forename: Barbara L F
authors.initials: BL
authors.lastname: Kaplan
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology; D001151:Arsenic / Q000633:toxicity; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D015703:Antigens, CD; D007075:Immunoglobulin M; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D001151:Arsenic