tacrolimus and Leukemia-Lymphoma--Adult-T-Cell

Human T-cell lymphotropic virus (HTLV) is the first discovered retrovirus causing malignancy in human. HTLV infection affects host's ocular tolerance and causes various diseases in the eye. Here we discuss the manifestations, mechanisms, treatments, and future directions of HTLV-related ocular diseases. RECENT FININGS: Recent serological researches showed that the number of HTLV-1 carriers in metropolitan area was increasing, although seroprevalence of HTLV-1 in general population was decreased after screening serological tests in blood donors started. The most common clinical entity of uveitis was still HTLV-1 uveitis in HTLV-1 highly endemic area, but prevalence of HTLV-1 uveitis varies in different parts of the world. As for treatment of inflammation, tacrolimus and 5-azacytidine were reported to be effective for autoimmune manifestations in HTLV-1-related overlap syndrome (deratomyositis/Sjogren's syndrome) and HTLV-1-related myelodysplastic syndrome. Interleukin-2 receptor targeted therapies improved scleritis in patients with adult T-cell leukemia/lymphoma caused by HTLV-1. Basic researches identified that HTLV-1 tax and HTLV-1 basic leucine zipper factor play critical roles in the HTLV-1-related disease and are now being investigated as targeted therapies.. Development of modern molecular biology makes it possible to reveal deep insights of HTLV-1-related ocular diseases. Although effective therapies based on basic researches have been reported, further endeavor is necessary to establish much more specific treatments of the ocular diseases.

Topics: Azacitidine; Enzyme Inhibitors; Human T-lymphotropic virus 1; Humans; Immunosuppressive Agents; Keratoconjunctivitis Sicca; Leukemia-Lymphoma, Adult T-Cell; Tacrolimus; Uveitis

Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre-T-cell receptor (TCR) signaling, TCR-mediated positive selection of thymocytes into mature T cells, and many aspects of the immune response. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as cyclosporin A (CsA) and FK506, are powerful immunosuppressants in wide clinical use. We observed sustained calcineurin activation in human B- and T-cell lymphomas and in all mouse models of lymphoid malignancies analyzed. In intracellular NOTCH1 (ICN1)- and TEL-JAK2-induced T-cell lymphoblastic leukemia, two mouse models relevant to human malignancies, in vivo inhibition of calcineurin activity by CsA or FK506 induced apoptosis of leukemic cells and rapid tumor clearance, and substantially prolonged mouse survival. In contrast, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression. Moreover, CsA treatment induced apoptosis in human lymphoma and leukemia cell lines. Thus, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a relevant therapeutic target in lymphoid malignancies.

Topics: Animals; Antineoplastic Agents; Calcineurin; Calcineurin Inhibitors; Cell Line, Tumor; Cyclosporine; Disease Models, Animal; Enzyme Activation; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma, B-Cell; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Oncogene Proteins, Fusion; Receptor, Notch1; Tacrolimus

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Disease Models, Animal; Enzyme Inhibitors; Leukemia-Lymphoma, Adult T-Cell; Mice; Tacrolimus

The immunosuppressive macrolide rapamycin is used in humans to prevent graft rejection. This drug acts by selectively repressing the translation of proteins that are encoded by an mRNA bearing a 5'-polypyrimidine tract (e.g., ribosomal proteins, elongation factors). The human immunodeficiency virus type 1 (HIV-1) carries a polypyrimidine motif that is located within the tat exon 2. Treatment of human T lymphoid cells with rapamycin resulted in a marked diminution of HIV-1 transcription when infection was performed with luciferase reporter T-tropic and macrophage-tropic viruses. Replication of fully infectious HIV-1 particles was abolished by rapamycin treatment. The rapamycin-mediated inhibitory effect on HIV-1 production was reversed by FK506. The anti-HIV-1 effect of rapamycin was also seen in primary human cells (i.e., peripheral blood lymphocytes) from different healthy donors. Rapamycin was shown to diminish basal HIV-1 long terminal repeat gene expression, and the observed effect of rapamycin on HIV-1 replication seems to be independent of the virus-specific transactivating Tat protein. A constitutive beta-actin promoter-based reporter gene vector was unaffected by rapamycin treatment. Kinetic virus infection studies and exposure to reporter viruses pseudotyped with heterologous envelope proteins (i.e., amphotropic murine leukemia virus and vesicular stomatitis virus G) suggested that rapamycin is primarily affecting the life cycle of HIV-1 at a transcriptional level. Northern blot analysis confirmed that this compound is selectively targeting HIV-1 mRNA synthesis.

Topics: Actins; Blotting, Northern; Gene Products, tat; Genes, Reporter; HIV Long Terminal Repeat; HIV-1; Humans; Immunosuppressive Agents; Indicators and Reagents; Leukemia-Lymphoma, Adult T-Cell; Plasmids; RNA, Messenger; Sirolimus; Tacrolimus; tat Gene Products, Human Immunodeficiency Virus; Transfection; Tumor Cells, Cultured; Virus Replication