title: A peripheral mechanism preserves self-tolerance to a secreted protein in transgenic mice.
abstract: We have examined mechanisms of tolerance to circulating self-proteins in mice that are transgenic for human insulin. Normal, nontransgenic mice develop serum antibody responses when injected with human insulin in CFA; syngeneic transgenic mice do not. B cell responsiveness was assessed by immunizing with human insulin coupled to a T-independent Ag, Brucella abortus. No differences were found in the numbers of insulin-specific splenic plaque-forming cells between transgenic and nontransgenic mice suggesting that insulin-specific B cells are not tolerant in transgenic mice. Similarly, APC from transgenic and nontransgenic mice display no differences in their ability to process and present human insulin to human insulin-specific T cells in vitro. However, marked differences were detected between transgenic and nontransgenic T cells. Lymph node T cells from transgenic mice primed with human insulin provided no detectable helper activity for secondary antibody responses to human insulin whereas, lymph node T cells from nontransgenic mice did. Nevertheless, lymph node T cells from transgenic mice developed significant proliferative responses to human insulin. Lymph node T cells obtained from transgenic and nontransgenic mice were fused to BW5147 and human insulin-specific T cell hybridomas were generated. The fact that human insulin-specific T cell hybridomas were obtained from the transgenic mice suggests that these T cells were not clonally deleted. In addition, APC from transgenic mice did not stimulate human insulin-specific hybridomas from normal mice in the absence of exogenous insulin. We suggest that T cells specific for human insulin are not deleted in the thymus of transgenic mice because APC in the thymus do not bear the requisite levels of endogenous human insulin/Ia complexes. Therefore, we conclude that tolerance in the transgenic mice is preserved by peripheral mechanisms.
authors.affiliation: Department of Pathology, Jewish Hospital of St. Louis, MO 63110.
authors.forename: P J
authors.initials: PJ
authors.lastname: Whiteley
authors.forename: N J
authors.initials: NJ
authors.lastname: Poindexter
authors.forename: C
authors.initials: C
authors.lastname: Landon
authors.forename: J A
authors.initials: JA
authors.lastname: Kapp
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology; D015139:Blotting, Southern; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006825:Hybridomas; D007108:Immune Tolerance; D007328:Insulin / Q000235:genetics / Q000276:immunology*; D008211:Lymphocyte Cooperation; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D011948:Receptors, Antigen, T-Cell