Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human T-cell lymphotrophic virus I (HTLV-I)-encoded tax plays a role in the early phases of HTLV-I-induced disease by deregulating the expression of the genes that encode interleukin-2 (IL-2) and the multisubunit (IL-2R alpha, IL-2R beta, and IL-2R gamma) IL-2 receptor (IL-2R). However, later in the course of the disease adult T-cell leukemia (ATL), cells no longer produce IL-2 yet continue to express the IL-2R. During studies to define the pathogenic mechanisms that underlie this IL-2-independent proliferation, we defined a cytokine designated IL-T/IL-15 that stimulates T-cell proliferation and requires the expression of IL-2R beta and IL-2R gamma for its action. To exploit the fact that IL-2Rs are present on abnormal T cells in patients with tropical parasitic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) and ATL but not on normal resting cells, different forms of IL-2R-directed therapy have been initiated. Unmodified humanized anti-Tac is being used to treat patient with TSP/HAM. To enhance its effector function for the treatment of ATL anti-Tac was armed with alpha- and beta-emitting radionuclides. In a clinical trial with 90Y-anti-Tac at the doses used (5, 10, and 15 mCi), 9 of the 18 patients with ATL underwent a partial or sustained complete remission. Thus the clinical application of IL-2R-directed therapy using a humanized monoclonal antibody or that antibody armed with radionuclides provides a new perspective for the treatment of autoimmune disorders such as TSP/HAM and certain neoplastic diseases including ATL.
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PMID:The promiscuous IL-2/IL-15 receptor: a target for immunotherapy of HTLV-I-associated disorders. 879 21

We describe the experience of The Royal London Hospital with human T-cell lymphotropic virus type 1 (HTLV-1) related disease. Twelve patients presented from 1988-1993, nine of them in 1993. None were born in the U.K. and 11 were of West Indian origin. Ten had overt lymphomas, one tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) and one atypical lymphocytosis and Strongyloidiasis. Five presented acutely ill to Casualty and three died shortly after presentation. Four had been referred to rheumatologists and five had predominantly gastrointestinal symptoms. The population of Caribbean origin served by the hospital is 23,700 and one would only expect one or two cases of lymphoma and one or two cases of TSP/HAM per year. Overall the spectrum of clinical disease at presentation was varied. Suspicion of HTLV-1 infection is merited in patients of West Indian origin between the ages of 30-65 years, who present with a sarcoid-like illness, gastrointestinal symptoms, leukaemia/lymphoma, myelopathy or myositis like-illness.
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PMID:Experience of human lymphotropic virus type I (HTLV-I) in an East London hospital. 885 49

Adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with differing patterns of immune dysfunction. Biomarkers of immune activation may correlate with perturbations of immune function associated with these diseases. We conducted a pilot cross-sectional study to assess four candidate biomarkers of immune activation. beta 2-microglobulin, neopterin, tryptophan, and kynurenine levels were assayed in stored sera from asymptomatic, human T-cell leukemia virus type I (HTL V-I)-seronegative (HTLV-I-) and HTLV-I-seropositive (HTLV-I+) individuals, and ATL and HAM/TSP patients previously enrolled in seroepidemiological studies in Jamaica. Mean levels of beta 2-microglobulin, neopterin, and kynurenine were significantly elevated among ATL patients compared to the other study groups. Mean tryptophan levels were significantly lower among ATL and HAM/TSP patients than HTLV-I- and HTLV-I+ groups. No significant differences in biomarkers were found between the HTLV-I- and HTLV-I+ groups. Among HAM/TSP patients, a significant association was found between elevated neopterin levels and symptoms of less than 4 years duration. In Cox proportional hazards regression modeling, neopterin and tryptophan were found to be independent predictors of survival among ATL patients. This study demonstrates a differential pattern of biomarkers of immune activation among ATL and HAM/TSP patients compared to HTLV-I- and HTLV-I+ individuals. Neopterin and tryptophan may be useful clinical indicators of disease severity and prognosis among HAM/TSP and ATL patients.
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PMID:Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma. 887 61

The genomic sequence of human T-cell leukemia virus type 1 (HTLV-1) is highly conserved, although minor sequence variations enable classification of the isolates into several subgroups. We previously reported, however, that the Tax-coding sequence of HTLV-1 genome is highly variable in a random fashion within individuals with HAM/TSP and asymptomatic carriers. Here, we describe frequent base substitutions in the LTR sequence similarly to those in Tax-coding sequence. These observations indicate that frequent mutations are not unique to the sequence encoding the most effective antigen for cytotoxic T lymphocytes, but also seen in the LTR, a non-coding sequence. Thus, frequent mutations seem to occur during the viral replication process rather than the selection of rare mutants by immune surveillance.
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PMID:Mutation rates in LTR of HTLV-1 in HAM/TSP patients and the carriers are similarly high to Tax/Rex-coding sequence. 902 6

We generated several lines of mice transgenic for the lacZ reporter gene under the control of an HTLV-I LTR. Two different LTR were used; one was isolated from a case of Adult T-cell Leukemia (ATL), the other from a case of Tropical Spastic Paraparesis (TSP/HAM). These LTR differed at 18 nucleotide positions. The pattern of expression of the transgene, studied at the RNA level by RT-PCR, was the same regardless of the origin of the promoter. The beta-galactosidase activity was detected primarily in the central nervous system, in the parenchyma, the choroid plexus and the ependymal cells along the ventricles. In parenchyma, double labelling experiments showed that the cells expressing beta-galactosidase were neurons. These results show that choroid plexus cells and ependymal cells, as well as some neurons, are permissive for the activity of the HTLV-I promoter. The origin of the LTR had not influence on the pattern of expression of the reporter gene.
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PMID:Analysis of the expression directed by two HTLV-I promoters in transgenic mice. 902 6

Human T-cell lymphotropic virus type-I (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). HAM/TSP and ATL occur infrequently among HTLV-I-infected individuals, and rarely develop in the same individual. To study host and viral factors involved in the induction, tissue tropism, as well as pathogenesis of HAM/TSP, peripheral blood lymphocytes (PBL) from 14 patients with HAM/TSP and from 9 controls were introduced into severe combined immunodeficiency (SCID) mice by intraperitoneal injection. Mice were followed for up to 26 weeks. Human IgG was produced from 2 to 14 weeks after reconstitution in all animals. Thirty-two of 44 mice (72%) showed circulating human antibody against the major viral protein products of HTLV-I. Analysis of viral sequences by polymerase chain reaction (PCR) demonstrated HTLV-I sequences in 21/38 (55%) brains and in 7/17 (41%) spinal cords from HTLV-I-hu SCID mice. No animal had clinical evidence of neurological impairment or pathological findings similar to those seen in HAM/TSP. Seven mice who received PBL from Epstein Barr virus (EBV)-seropositive patients developed an intraperitoneal lymphoma. In 2 mice an infiltration of brain by a lymphoblastic tumor of B/T cell type was observed. By PCR, all the tumors were EBV-positive; HTLV-I sequences were detected in 5 of them. Our study suggests that the HTLV-I-hu-SCID mouse provides a potentially valuable system for studying the production, kinetics, and pathogenicity of anti-HTLV-I antibody, and may help clarify the interaction of EBV and retroviruses in the development of disease.
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PMID:Human T-cell lymphotropic virus type-I infection in the severe combined immunodeficiency mouse. 899 39

We describe the clinical and pathological features of 23 Afro-Caribbean patients with adult T-cell leukaemia/lymphoma admitted to the Queen Elizabeth Hospital, Barbados over a 5 year period. There were 9 males and 14 females, with a median age of 38 years (range 14-84). Twelve had acute leukaemia, 10 lymphoma (including 4 with solitary extra nodal lesions) and 1 smouldering subtype. Two patients had a past history of tropical spastic paraparesis/HTLV I associated myelopathy (TSP/HAM). The prognosis was poor, with only 3 complete responses to chemotherapy (CHOP) lasting from 9 to 36 months. We conclude that ATLL in Barbados is similar to the disease in the other Caribbean islands and Japan, except that in Barbados the age of onset is over a decade younger than in Japan.
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PMID:Clinical and laboratory features of adult T-cell leukaemia lymphoma in Barbados. 903 Oct 87

Human T-lymphotropic virus type I (HTLV-I) was the first retrovirus which was directly associated with adult T-cell leukemia (ATL). Infection with HTLV-I can also lead to various other diseases, e.g. HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-I uveitis, possibly via induction of immunodeficiency or hyperreactivity against HTLV-I-infected cells. Epidemiological data have shown that patients who developed these diseases represent a small percentage of HTLV-I-infected individuals living in restricted geographical areas. The identification of HTLV-I-infected individuals using serological and DNA-diagnostic methods is important because knowledge of HTLV-I seropositivity may help to prevent the transmission between sexual partners, as well as transmission from mother to child and blood transfusion. It also assists in establishing a diagnosis of ATL, HAM/ TSP and other HTLV-I-associated diseases.
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PMID:DNA diagnosis of HTLV-I. 905 68

Since the presence of anti-p53 antibody has been correlated with the mutation and accumulation of p53, the aim of this study was to detect anti-p53 antibody and understand its correlations with anti-Tof, -Rex, or -Tax antibody reactivity in HTLV-I infected people differing in their clinical status. A plasmid (pGEX-Tof) was constructed to express Tof recombinant protein (RP) in Escherichia coli. Serum samples from 50 asymptomatic carriers (ACs), 50 adult T-cell leukemia (ATL) and 50 HTLV-I-associated myelopathyltropical spastic paraparesis (HAM/TSP) patients were assayed for reactivity with different RPs by Western immunoblotting. The results showed that 2% of ACs, 4% of ATL patients and 6% of HAM/TSP patients had anti-p53 antibody. Therefore, anti-p53 antibody is not a useful serological marker for clinical management of HTLV-I infected people. Only 1 HAM/TSP patient had anti-Tof antibody whose specificity was further confirmed by antibody competition enzyme immunoassay. This study demonstrates that Tof protein is immunogenic in vivo, suggesting that it plays a role in the life cycle and pathogenesis of HTLV-I. The rate of anti-Rex antibody among HAM/TSP patients was significantly higher than that of ACs or ATL patients. In addition, 50% of ACs, 42% of ATL and 98% of HAM/TSP patients had anti-Tax antibody. McNemar's test showed that the presence of anti-p53 antibody did not have any correlation with the anti-Tax antibody in HTLV-I-infected people, while the correlation between anti-p53 and anti-Rex antibodies or anti-p53 and anti-Tof antibodies cannot be ruled out in this study.
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PMID:Antibody reactivities to tumor-suppressor protein p53 and HTLV-I Tof, Rex and Tax in HTLV-I-infected people with differing clinical status. 913 42

Fas/APO-1 mediates apoptosis via Fas and Fas ligand transduction. Recently, a soluble form of Fas (sFas) was described which seems to be functionally implicated in the Fas signal system, suggesting a relationship between some disorders and sFas function. We measured sFas-levels in sera from normal controls and patients with disorders linked to human retroviral infection of human immunodeficiency virus (HIV) and human T-cell leukemia virus type-1 (HTLV-1). The sFas level of normal controls. HTLV-1 carriers seronegative for HIV, and patients with HTLV-1 associated myelopathy/tropical paraparesis (HAM/TSP), adult T-cell leukemia (ATL), and AIDS was 1.62 +/- 0.49, 1.90 +/- 0.49, 2.00 +/- 0.59, 3.32 +/- 2.05, and 3.06 +/- 0.92 ng/ml, respectively. Although the level of sFas in patient groups with HAM/TSP, ATL, and AIDS was significantly high in comparison to that of normal controls (p < 0.01), the individual values were highly variable within the groups. The sFas level was statistically correlated to the soluble interleukin-2 receptor (sIL-2R) level, as well as to cells expressing membrane Fas (mFas), indicating the same cellular origin. In some ATL cases, however, serum sFas levels and mFas expression density on leukemic T-cells were discrepant, with especially high levels of the soluble form and a lack of expression of the membrane form observed in 2 cases, sFas detection could serve as a putative marker for active diseases in patients with ATL and AIDS.
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PMID:Serum levels of soluble Fas/APO-1 receptor in human retroviral infection and associated diseases. 914 6


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