Selective immunomodulation by the autoimmunity-inducing xenobiotics streptozotocin and HgCl2.
Exposure to certain drugs and environmental chemicals can provoke the onset of autoimmune disease in susceptible individuals by releasing (self) epitopes for which tolerance has not been established, while simultaneously providing the necessary adjuvant activity. The resulting response type is influenced by the genotype of exposed individuals and relates to susceptibility to the adverse immune effects of the chemicals. Here, we assessed the modulatory role of the chemical compounds themselves. A single injection of streptozotocin (STZ) increased the number of CD8+ cells, macrophages, apoptotic cells, and IFN-gamma-producing T helper and T cytotoxic cells, whereas the number of CD4+ cells and B cells was reduced in the draining lymph node. Coinjection with the reporter antigen TNP-OVA resulted in primary and secondary production of TNP-specific antibodies that were predominantly of IgG2a and IgG2b isotype, whereas STZ did not enhance priming for delayed-type hypersensitivity (DTH) responses to TNP-OVA. Injection of HgCl2 on the other hand, reduced the number of IFN-gamma-producing cells, induced accumulation of B cells and CD4+ and CD8+ T cells, enhanced IgG1 and IgE production to TNP-OVA, and primed for secondary IgG1 and IgE production as well as for DTH reactions. Together these results indicate that a single injection of STZ stimulates type-1 responses, whereas HgCl2 enhanced mixed type-1 and -2 responses in BALB/c mice. These response types match the (auto)immune effects elicited to unknown (auto)antigens following multiple injections of these chemicals.
Albers
R
R
Research Institute for Toxicology, Utrecht University, The Netherlands.
de Heer
C
C
Bol
M
M
Bleumink
R
R
Seinen
W
W
Pieters
R
R
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005362:Ficoll / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D008627:Mercuric Chloride / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D013311:Streptozocin / Q000008:administration & dosage / Q000276:immunology*; D014301:Trinitrobenzenes / Q000008:administration & dosage / Q000276:immunology; D015262:Xenobiotics / Q000008:administration & dosage / Q000276:immunology*
D000276:Adjuvants, Immunologic; D006241:Haptens; C020529:TNP-ficoll; D014301:Trinitrobenzenes; D015262:Xenobiotics; C038600:trinitrophenyl-ovalbumin; D005362:Ficoll; D008627:Mercuric Chloride; D013311:Streptozocin; D010047:Ovalbumin