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Sensitivity of activated human lymphocytes to cyclosporine and its metabolites

Zeevi, A and Venkataramanan, R and Burckart, G and Wang, CP and Murase, N and Van Thiel, DH and Starzl, TE and Makowka, L and Duquesnoy, RJ (1988) Sensitivity of activated human lymphocytes to cyclosporine and its metabolites. Human Immunology, 21 (2). 143 - 153. ISSN 0198-8859

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Alloreactive T cells generated as clones from mixed lymphocyte cultures, or propagated from heart or liver transplant biopsies, were tested for secondary proliferation measured in the primed lymphocyte test in the presence of Cyclosporine A and metabolites fractionated from human bile. Significant differences were observed in Cyclosporine A sensitivity between various cell cultures ranging as high as 100-fold. The liver is the primary site of Cyclosporine A metabolism, which yields a number of hydroxylated and N-dimethylated derivatives that are eventually secreted into the bile. Bile was collected from adult liver transplant patients on Cyclosporine A therapy and following extraction with diethyl ether, separated by high pressure liquid chromatography. Thirteen fractions were tested for their effect on lymphocyte proliferation in concanavalin A activation, mixed lymphocyte cultures and primed lymphocyte test assays. The strongest immunosuppressive effect was found with fraction 8, which contained metabolite M17, which has a single hydroxylation in position 1. Only three other fractions 9, 10, and 13, which contained metabolites M1, M18, and M21, respectively, exhibited immunosuppressive activity, albeit much lower than that of Cyclosporine A. Differences in Cyclosporine A sensitivity among alloreactive T cells followed similar patterns with Cyclosporius A metabolites. Thus, the assessment of the Cyclosporine A effect must consider differences in drug sensitivity of lymphocytes involved in transplant immunity and the generation of metabolites with immunosuppressive activity. © 1988.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Zeevi, A
Venkataramanan, Rrv@pitt.eduRV
Burckart, G
Wang, CP
Murase, N
Van Thiel, DH
Starzl, TEtes11@pitt.eduTES11
Makowka, L
Duquesnoy, RJ
Centers: Other Centers, Institutes, Offices, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 1988
Date Type: Publication
Journal or Publication Title: Human Immunology
Volume: 21
Number: 2
Page Range: 143 - 153
DOI or Unique Handle: 10.1016/0198-8859(88)90089-4
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0198-8859
Other ID: uls-drl:31735062130319, Starzl CV No. 881
Date Deposited: 08 Apr 2010 17:15
Last Modified: 04 Feb 2019 15:57


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