Immunomodulatory effects of nitrosoureas on the phenotype and functions of T cells in the thymus and periphery.
We have recently demonstrated that nitrosoureas such as 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and chlorozotocin (CLZ) can cure almost 100% of mice bearing LSA tumor, syngeneic to C57BL/6 mice. In contrast, similar or higher doses of streptozotocin (STZ) completely failed to cure LSA-bearing mice. Further studies revealed that the efficacy of nitrosoureas may depend on their immunomodulating properties. In the current study, therefore, we investigated the effect of these nitrosoureas on the immune system of normal mice. Treatment of C57BL/6 mice with 5 intraperitoneal injections of 20 mg/kg body weight of BCNU or CLZ caused an increase in the percentage of CD4(-)CD8- T cells and a decrease in the percentage of CD4(+)CD8+ T cells in the thymus. In addition, such treatment also caused an increase in the percentage of CD4+ T cells without significantly affecting the CD8+ T cells in the thymus. However, when total cellularity of the thymus was studied, BCNU and CLZ were found to decrease the total number of CD4(+)CD8+ T cells without significantly affecting the other subsets. In contrast, similar or higher (100 mg/kg body weight) doses of STZ had no significant effect on the total number and percentages of T cell subsets in the thymus. Also BCNU and CLZ but not STZ treatment caused a 50% decrease in the total number of CD4+ and CD8+ T cells in the spleen. When T cells in the spleens of nitrosourea-treated mice were functionally analysed, it was observed that BCNU and CLZ caused a dramatic decrease in the T cell responsiveness to ConA, anti-CD3 and phorbol myristate acetate plus calcium ionophore stimulation. In contrast, STZ treatment failed to significantly inhibit the T cell responsiveness to these activation signals. Using the accessory cell-dependent and -independent assays, BCNU and CLZ were found to suppress the functions of both T cells and macrophages. Also, addition of growth factors such as IL-1, IL-2, IL-4 and IL-6 failed to reconstitute the defective responsiveness of BCNU- and CLZ-treated T cells and macrophages. Together our data suggest that nitrosoureas have varying immunomodulating properties and this may in turn determine their efficacy in the treatment of cancer.
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Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Nagarkatti
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Nagarkatti
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D000276:Adjuvants, Immunologic; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002330:Carmustine / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D013311:Streptozocin / Q000031:analogs & derivatives / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000502:physiology
D000276:Adjuvants, Immunologic; D009607:Nitrosourea Compounds; C007028:chlorozotocin; D013311:Streptozocin; D002330:Carmustine