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The Application of an in Vitro Cytotoxicity Test to Studies of the Effects of Drugs on the Cellular Immune Response in Mice

I. Primary Response¹

From the Division of Oncology, University of Washington School of Medicine, Seattle, Washington 98195

Abstract

An in vitro assay for cytotoxic cellular immunity has recently been developed based on the release of ⁵¹Cr from labeled target cells killed by specifically sensitized allogeneic lymphocytes. This test was applied to studies of the effects of chemotherapeutic agents on cellular immunity in mice. Adult C57BL/6 mice (H-2^b) were inoculated with x-irradiated ascitic lymphoma cells (LSTRA) of BALB/c origin (H-2^d) on day 0 and their spleen cells tested for reactivity against labeled LSTRA cells 4 to 10 days later. Each test was performed on quadruplicate samples with the standard error of the mean being less than 2%. In mice immunized with LSTRA cells but not given drugs a peak cytotoxicity of 16% was observed on day 6. Cells from mice treated on day +1 with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 48 mg/kg cyclophosphamide (CY) or CY 180 mg/kg exhibited a peak reactivity of 41%, 12% and 2%, respectively, while drug administration on day -1 resulted in a peak reactivity of 36%, 33% and 23%, respectively. The results show that this test can be used to study the effects of drugs on the cellular immune response and that the timing of the drug and antigen administration, as well as the dose of drug, are critical. The increased cytotoxic reactivity of lymphocytes from drug-treated immunized mice suggests that although chemotherapeutic agents may be immunosuppressive as assayed in vivo, the activity of a given number of surviving lymphoid cells when tested in vitro and compared with the same number of cells from immunized but non-drug-treated hosts may be increased.

Footnotes

¹ This work was supported by Grants CA 10777, CA 19895 and CA 05231 from the National Cancer Institute, National Institutes of Health, United States Public Health Service, and the Institutional Cancer Grant IN-26 from the American Cancer Society.

² Special Fellow of the Leukemia Society of America.

³ Scholar of the Leukemia Society of America.