tacrolimus and Leukemia--T-Cell

Topics: Female; Fetal Blood; Graft vs Host Disease; Humans; Leukemia, T-Cell; Lymphoma, T-Cell; Methotrexate; Middle Aged; Skin Neoplasms; Stem Cell Transplantation; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Whole-Body Irradiation

To report a case of elevated blood tacrolimus concentration after application of topical tacrolimus ointment in an erythrodermic patient.. A 44-year-old man developed generalized erythroderma and itching due to infection with human T-cell lymphotropic virus. Despite application of strong glucocorticosteroid ointments, the symptoms and area of erythroderma were not alleviated. Daily topical application of tacrolimus 0.1% ointment was added and therapeutic drug monitoring was started. The dose and applied area of tacrolimus were gradually increased from 2.5 to 12.5 g/d and from 10% to 90% of body surface area, respectively. Because the trough concentration of tacrolimus in whole blood increased from 7.5 ng/mL on treatment day 9 to 15.4 ng/mL on day 13, the dose was reduced to 10 g/d. However, the concentration further elevated to 16.5 ng/mL. Therefore, the applied area was reduced to 20% of body surface area, and the tacrolimus concentration decreased gradually thereafter. Although the transient increase of blood tacrolimus concentration was observed on day 23, treatment with 20% applied area and 5 g/d were maintained.. Topically applied tacrolimus was substantially absorbed with the expansion of its applied area and dose. Increased tacrolimus concentrations may have a tendency to depend on the increase of the percent of body surface area per dose. Our findings showing the elevation of blood tacrolimus concentration after application of the ointment to a large area of the body suggest that the applied area should be as narrow as possible in a barrier-disrupted condition such as erythroderma. However, the safety of tacrolimus ointment has not been established in patients with generalized erythroderma.. Tacrolimus concentrations in whole blood should be carefully monitored to prevent nephrotoxicity. Based on the results of that monitoring, the application area and dose of tacrolimus ointment should be closely adjusted, especially in generalized erythrodermic cases.

Topics: Administration, Topical; Adult; Deltaretrovirus Infections; Dermatitis, Exfoliative; Humans; Leukemia, T-Cell; Male; Ointments; Pruritus; Skin Absorption; Tacrolimus; Time Factors

The Fas (CD95) antigen plays a key role in regulating T-cell activation and survival. We have generated a Fas-resistant subclone of the human T-cell leukaemia line, H9, which is still able to undergo apoptosis in response to T-cell receptor ligation. Molecular analyses revealed that resistance to Fas-mediated apoptosis was due to a heterozygous mutation in the death domain of the Fas gene which generates a stop codon, and thus encodes a truncated Fas molecule. Fas ligation was able to induce apoptosis in the presence of cycloheximide, indicating that the mutant Fas molecule retained some signalling capability, which is death-domain independent. These cells will provide a useful tool for dissecting the complexities of Fas signalling pathways.

Topics: Amino Acid Sequence; Apoptosis; Cycloheximide; fas Receptor; Humans; Leukemia, T-Cell; Molecular Sequence Data; Mutation; Neoplastic Stem Cells; Receptors, Antigen, T-Cell; Tacrolimus; Tumor Cells, Cultured

We evaluated the efficacy of a new purine nucleoside phosphorylase inhibitor, BCX-34, as an immunosuppressive agent. BCX-34 showed a complete inhibitory effect on the proliferation of T-cells in an in vitro system, whereas no influence was observed in B-cell lines. In addition, it was revealed that this inhibitory effect was not due to the suppression of interleukin-2 production. Therefore, BCX-34 might be a potentially useful drug that can be used in combination, not competition, with cyclosporine A and FK506.

Topics: Animals; B-Lymphocytes; Cell Division; Cells, Cultured; Cyclosporine; Drug Synergism; Guanine; Humans; Immunosuppressive Agents; Interleukin-2; Jurkat Cells; Leukemia, T-Cell; Mice; Purine-Nucleoside Phosphorylase; T-Lymphocytes; Tacrolimus; Tumor Cells, Cultured

FK506, an immunosuppressant, inhibits the production of several cytokines in T lymphocytes. We observed that FK506 suppressed the transcription of a chemotactic cytokine, interleukin-8 (IL-8) in a human T cell line, Jurkat cells, activated by phorbol 12-myristate 13-acetate (PMA) and calcium (Ca2+) ionophore (ionomycin). By deleted and mutated analysis of the IL-8 promoters, the AP-1 and kappa B-like sites were identified as the responsive elements for PMA and ionomycin. FK506 suppressed the transcriptions through the AP-1 or kappa B-like sites induced by PMA plus Ca(2+)-mobilizing agents, but not those induced by Ca(2+)-independent stimuli. In gel retardation analysis, FK506 had little effect on the binding to the AP-1 site of PMA/ionomycin-induced nuclear factors, which were recognized with anti-JunD or c-Fos antibody. In contrast, FK506 or EGTA (Ca2+ chelator) similarly affected the formation of kappa B-like site binding complexes, which were not recognized by any antibodies against the human Rel family proteins (c-Rel, p65, p50, and p49). Furthermore, we confirmed the previous report that FK506 suppressed the PMA/ionomycin-induced activation through authentic kappa B site of immunoglobulin (Ig) gene, to which NF-kappa B binding was also decreased by FK506, indicating that both IL-8 kappa B-like site and Ig kappa B site are FK506-sensitive in spite of the difference of binding factors. Our results indicate that not only the reported IL-2 NF-AT and NFIL-2A sites and Ig kappa B site, but also the IL-8 AP-1 and kappa B-like sites are terminals of FK506-sensitive pathway involving Ca2+ mobilization.

Topics: Base Sequence; Binding Sites; Calcium; Cell Line; Chloramphenicol O-Acetyltransferase; Enzyme-Linked Immunosorbent Assay; Gene Expression; Humans; Interleukin-8; Ionomycin; Kinetics; Leukemia, T-Cell; Luciferases; Molecular Sequence Data; NF-kappa B; Polymerase Chain Reaction; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun; Sequence Deletion; Suppression, Genetic; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate; Transcription, Genetic; Transfection; Tumor Cells, Cultured

Topics: Cell Division; Cell Line; Cyclosporine; Dose-Response Relationship, Drug; Humans; Kinetics; Leukemia, T-Cell; Tacrolimus