The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotrophic virus-I (HTLV-I). It is an aggressive leukemia with an overall mortality rate of 50% within 5 months; no conventional chemotherapy regimen appears successful in inducing long-term disease-free survival in ATL patients. However, ATL cells constitutively express high-affinity interleukin-2 receptors (IL-2Rs) identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference in receptor expression, we administered anti-Tac intravenously (IV) to 19 patients with ATL. In general the patients did not suffer untoward reactions, and in 18 of 19 cases did not have a reduction in normal formed elements of the blood. Seven patients developed remissions that were mixed (1 patient), partial (4 patients), or complete (2 patients), with partial and complete remissions lasting from 9 weeks to more than 3 years as assessed by routine hematologic tests, immunofluorescence analysis, and molecular genetic analysis of T-cell receptor gene rearrangements and of HTLV-I proviral integration. Furthermore, remission was associated with a return to normal serum calcium levels and an improvement of liver function tests. Remission was also associated in some cases with an amelioration of the profound immunodeficiency state that characterizes ATL. Thus the use of a monoclonal antibody that blocks the interaction of IL-2 with its receptor expressed on ATL cells provides a rational approach for treatment of this aggressive malignancy.     

Cell-type-specific transactivation of the parathyroid hormone-related protein gene promoter by the human T-cell leukemia virus type I (HTLV-I) tax and HTLV-II tax proteins

The human T-cell leukemia virus type I (HTLV-I) and HTLV-II Tax proteins are potent transactivators of viral and cellular gene expression. Using deletion mutants, the downstream parathyroid hormone-related protein (PTHrP) promoter is shown to be responsive to both HTLV-I and HTLV-II Tax as well as the AP1/c-jun proto-oncogene. Transactivation of PTHrP by Tax was seen in T cells but not in B-cell lines or fibroblasts. A carboxy terminal Tax deletion mutant was deficient in transactivation of both the PTHrP and IL2R alpha promoters but not the HTLV-I long terminal repeat (LTR). Exogenous provision of NFkB rescued IL2R alpha expression but not the PTHrP promoter. Thus, HTLV-I Tax, HTLV-II Tax, and c-jun transactivate PTHrP and may contribute to the pathogenesis of hypercalcemia in adult T-cell leukemia.     

Cytokine expression and tumorigenicity of large granular lymphocytic leukemia cells from mice transgenic for the tax gene of human T-cell leukemia virus type I

The human T-cell leukemia virus type I (HTLV-I) regulatory protein, Tax, has been speculated to play a major role in HTLV-I leukemogenesis. Indeed, several studies have suggested that upregulation of various cellular oncogenes and cytokines by Tax may explain the pathogenesis observed in HTLV-I-infected individuals, as well as several Tax-transgenic animal models. We report here the analysis of cytokine expression in a Tax-transgenic animal model with large granular lymphocytic (LGL) leukemia. Two different transgenic mice showed identical expression of interleukin-1alpha (IL-1alpha), IL-1beta, interferon gamma (IFNgamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in peripheral tail tumors. Interestingly, LGL cell lines derived from these same tumors expressed high levels of both IFNgamma and GM-CSF, which correlated with the level of Tax expression. These same LGL cell lines also expressed high levels of lymphocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1). Engraftment of these LGL cell lines into severe combined immunodeficient (SCID) mice led to the development of leukemia and lymphomas. Examination of these SCID mice showed that their pathology was nearly identical to that observed in the original Tax-transgenic mouse model. Both the Tax-transgenic and engrafted SCID mouse models allow for the analysis of cellular events that are required for tumor development associated with HTLV infection and suggest that Tax expression may be responsible for the upregulation of certain cytokines and adhesion molecules that affect the infiltrating capabilities of HTLV-I-infected cells.     

Detection of HTLV-1 by polymerase chain reaction in situ hybridization in adult T-cell leukemia/lymphoma

A method for nonradioactive polymerase chain reaction in situ hybridization was developed and used to determine the distribution of human T-lymphotropic virus type I (HTLV-I) proviral DNA in paraffin-embedded surgical specimens of adult T-cell leukemia/lymphoma (ATLL). As controls, we used biopsy samples of five cases of mycosis fungoides, cells of an HTLV-I-infected cell line (MT2), as well as HTLV-1-negative cells (YAS). We successfully detected the amplicon of the HTLV-1 tax sequence in the nuclei of the cutaneous infiltrating lymphoid cells in 90% (9/10) of ATLL cases. Studies also revealed the existence of HTLV-1 provirus DNA in nuclei of sweat gland epithelial cells and vascular endothelial cells as well as lymphoid cells in ATLL patients. Mycosis fungoides and YAS cells were negative for the HTLV-I tax sequence, but MT2 cells were strongly positive. The results indicated that this technique was more sensitive in detecting intracellular amplicons than was the previous in situ hybridization method. Through its use, we were able to easily determine the distribution of HTLV-I-positive cells among the various cells and tissues of paraffin-embedded archival materials.     

T-cell malignancies in Brazil. Clinico-pathological and molecular studies of HTLV-I-positive and -negative cases

T-cell malignancies in Brazil have a high seroprevalence rate of HTLV-I antibodies. We have analyzed the disease features in 188 Brazilian patients with a T-cell disorder. These included 40 with T-lymphoblastic leukaemia or lymphoma (T-ALL/T-LbLy) and 148 with mature T-cell diseases: 5 T-prolymphocytic leukaemia, 53 adult T-cell leukaemia/lymphoma (ATLL), 54 cutaneous T-cell lymphomas, 29 pleomorphic T-cell lymphomas and 7 large granular lymphocyte leukaemia. The diagnosis was based on clinical, morphological and immunological features and HTLV-I serology. ATLL in Brazil has the same diseases features as in other endemic regions, the only apparent differences being: age, Brazilian patients being younger than Japanese, and ethnic grouping, one third of Brazilians being white Caucasians of European descent. We applied a scoring system based on the presence or absence of typical features associated with ATLL; hypercalcaemia, cell morphology, immunophenotype, histopathology and HTLV-I status, to see whether it may help in diagnosing cases of ATLL. All had high scores, whereas all other T-cell diseases scored low. Only 5 ATLL cases were HTLV-I-negative by serology, but they had otherwise typical features of ATLL, and their cells did not have HTLV-I proviral sequences by DNA analysis. Such cases suggest that ATLL may develop in a minority of individuals living in regions where it is endemic, without evidence of HTLV-I infection, and that other factors may contribute to the pathogenesis of the disease.     

Human immature thymocytes as target cells of the leukemogenic activity of human T-cell leukemia virus type I

The risk of developing adult T-cell leukemia (ATL) associated with neonatal infection by human T-cell leukemia virus type I (HTLV-I) suggests that early events triggered by HTLV-I might be of crucial importance in initiating the multistep lymphoproliferative process leading several decades later to the development of leukemic disease. Thus, infection of thymocytes early in life might be directly correlated with the development of ATL. In the present study, we show that in vitro infection of mature (CD2+CD3+) or immature (CD2+CD3-) thymocytes resulted in the exogenous interleukin (IL)-2-dependent proliferation of HTLV-I-positive thymocytes, most of them displaying a CD2+CD3-CD4+ phenotype and expressing the CD25 molecule, the alpha chain of the IL-2 receptor. Furthermore, the CD80 and CD54 antigens, normally expressed by thymic stromal cells, were detected on these transformed thymocytes, indicating that HTLV-I infection may disturb the cooperation between thymocytes and their thymic environment. These HTLV-I-positive thymocytes were producing significant amounts of IL-6, which was found to be implicated in their proliferation and in the expression of CD25, as demonstrated by blocking experiments using a monoclonal antibody to IL-6. The present study suggests that immature thymocytes may provide an environment favorable to the unfolding of events leading to leukemia.     

An inter district quality partnership: the experience of a large rural health service

The interleukin-2 receptor (IL-2R) gamma chain (gamma c chain) is shared by IL-4R, IL-7R, IL-9R, and IL-15R and plays an important role in regulation of the immune system. However, its regulation in monocytic cell lines has not been well clarified. We examined the expression and regulation of the IL-2R alpha, IL-2R beta, gamma c chain, IL-4R and IL-7R mRNA in a human monoblastic leukemia cell line, THP-1. Unstimulated THP-1 cells constitutively expressed a low level of gamma c chain and IL-4R mRNA. Phorbol myristate acetate (PMA) induced macrophage-like differentiation and up-regulated the gamma c chain mRNA expression in THP-1 cells. This effect of PMA was suppressed by the protein kinase inhibitors H-7 and staurosporine. PMA did not affect the expression of the other IL-R mRNAs examined. 1 alpha, 25(OH)2D3 and interferon-gamma also induced differentiation of THP-1 cells, but these reagents did not affect the expression of the IL-R mRNAs in THP-1 cells. These findings suggest that the expression of the gamma c chain mRNA is regulated by the PMA-dependent pathway and is not associated with that of the other IL-R mRNAs.