Inverse correlation of cyclosporine binding with sensitivity and resistance.
The primary effects of CsA on human lymphocyte responses in vitro appear to be the inhibition of IL-2 production and the inhibition of cytotoxic T cell activation. Induction of suppressor T cell activity is resistant to the effects of CsA. These data imply two distinct subsets of lymphocytes: CsA-resistant and CsA-sensitive. The current studies used a bioactive, dansylated derivative of CsA (dans-CsA), which is fluorescent, to assess binding of CsA at the single-cell level by flow cytometry. The results demonstrate that two populations of cells can be distinguished based on differential staining with dans CsA--a weakly staining subset and a population that binds intensely. Both subsets consist of CD4 (helper) and CD8 (cytotoxic/suppressor) T lymphocytes. Functional analysis revealed that the weakly staining subset consists of IL-2-producing T cells and precursor cytotoxic T lymphocytes. On the other hand, the intensely staining subset includes T cells that suppress in an antigen-specific manner after activation with alloantigen. Further studies showed that the weakly staining subset is markedly sensitive to the immunosuppressive effects of CsA in a PHA stimulation assay, while the intensely binding population is markedly resistant, requiring 10- to 100-fold more CsA to inhibit the PHA response. These studies suggest that sensitivity and resistance to CsA is inversely correlated with binding.
Hess
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AD
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Colombani
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PM
D000943:Antigens, Differentiation / Q000032:analysis; D003524:Cyclosporins / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004351:Drug Resistance; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008214:Lymphocytes / Q000145:classification / Q000378:metabolism* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D013696:Temperature
D000943:Antigens, Differentiation; D003524:Cyclosporins; D007376:Interleukin-2