Osteopontin-integrin interaction as a novel molecular target for antibody-mediated immunotherapy in adult T-cell leukemia.

BACKGROUND: Adult T-cell leukemia (ATL) is a CD4(+) T-cell neoplasm with a poor prognosis. A previous study has shown that there is a strong correlation between the secreted matricellular protein osteopontin (OPN) level and disease severity in ATL patients. Here, we investigated the role of OPN in ATL pathogenesis and the possible application of anti-OPN monoclonal antibody (mAb) for ATL immunotherapy in NOD/Shi-scid,IL-2Rg (null) (NOG) mice. RESULTS: Subcutaneous inoculation of ATL cell lines into NOG mice increased the plasma level of OPN, which significantly correlated with metastasis of the inoculated cells and survival time. Administration of an SVVYGLR motif-recognizing anti-OPN mAb resulted in inhibition not only of tumor growth but also of tumor invasion and metastasis. The number of fibroblast activating protein-positive fibroblasts was also reduced by this mAb. We then co-inoculated mouse embryonic fibroblasts (MEFs) isolated from wild-type (WT) or OPN knockout mice together with ATL-derived TL-OmI cells into the NOG mice. The mice co-inoculated with WT MEFs displayed a significant decrease in survival relative to those injected with TL-OmI cells alone and the absence of OPN in MEFs markedly improved the survival rate of TL-OmI-inoculated mice. In addition, tumor volume and metastasis were also reduced in the absence of OPN. CONCLUSION: We showed that the xenograft NOG mice model can be a useful system for assessment of the physiological role of OPN in ATL pathogenesis. Using this xenograft model, we found that fibroblast-derived OPN was involved in tumor growth and metastasis, and that this tumor growth and metastasis was significantly suppressed by administration of the anti-OPN mAbs. Our findings will lead to a novel mAb-mediated immunotherapeutic strategy targeting against the interaction of OPN with integrins on the tumor of ATL patients.

The incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type 1 carriers in Japan.

Human T-lymphotropic virus type 1 (HTLV-1) is highly endemic in the Kyushu/Okinawa region of Japan. A nationwide investigation verified the frequency of HTLV-1 carriers among first-time blood donors and the occurrence of newly diagnosed adult T-cell leukemia/lymphoma (ATL) cases from 2007 through 2008. After adjusting for differences in capture rate between areas, the age-, sex- and area-specific incidence of ATL among carriers was determined. Annual ATL incidence among 10 000 carriers was 7.7 and 8.7 for the Kyushu and non-Kyushu/Okinawa regions, respectively. The incidence increased sharply for men from their 40s to their 70s, but the rate in females remained unchanged through their 40s to 70s. ATL incidence in middle-aged females was still low, even if female carrier frequency was assumed to be identical to that of males. Patients with ATL in their 60s and 70s will comprise two-thirds of all patients with ATL for the next 15 years in Japan.

Relationships of diverse apoptotic death process patterns to mitochondrial membrane potential (Δψ(m)) evaluated by three-parameter flow cytometric analysis.

Recently, it has been proposed that novel methodologies are needed to re-evaluate apoptotic cell death, as studies of apoptosis have shown it to be a complex process. Since mitochondria are key regulators in cell death pathways, we developed a simultaneous 3-parameter flow cytometric analysis that incorporates the change in mitochondrial membrane potential (Δψ(m)) in an Annexin-V [for phosphatidyl-serine (PS)] and propidium iodide (PI) assay system (3 parameters with 4 colours), and evaluated the apoptotic process using various haematological malignant cell lines and death triggers. The present method enabled visualization of cell composition during apoptosis and captured complicated molecular events. For example, apoptotic cells that lost Δψ(m) did not always externalize PS, while some late apoptotic cells had polarized Δψ(m). The findings of unchanged PS-externalization and aberrant cell death suggest that there is no relationship of PS externalization and apoptosis with an unknown apoptotic mechanism. Based on PS-externalization, sensitivity to staurosporine, and the combination of cell lines and triggers, the apoptotic process was classified into 2 types. Importantly, most of our findings could not be observed by PS-PI and Δψ(m) assays when independently performed. Our method may be useful for examining mitochondrial-related apoptosis and death signalling pathways, as well as screening novel apoptosis-inducing cancer drugs.

Paradoxical expression of IL-28B mRNA in peripheral blood in human T-cell leukemia virus type-1 mono-infection and co-infection with hepatitis C virus.

BACKGROUND: Human T-cell leukemia virus type-1 (HTLV-1) carriers co-infected with and hepatitis C virus (HCV) have been known to be at higher risk of their related diseases than mono-infected individuals. The recent studies clarified that IL-28B polymorphism rs8099917 is associated with not only the HCV therapeutic response by IFN, but also innate immunity and antiviral activity. The aim of our research was to clarify study whether IL-28B gene polymorphism (rs8099917) is associated with HTLV-1/HCV co-infection. RESULTS: The genotyping and viral-serological analysis for 340 individuals showed that IL-28B genotype distribution of rs8099917 SNP did not differ significantly by respective viral infection status. However, the IL-28B mRNA expression level was 3.8 fold higher in HTLV-1 mono-infection than HTLV-1/HCV co-infection. The high expression level was associated with TT (OR, 6.25), whiles the low expression was associated with co-infection of the two viruses (OR, 9.5). However, there was no association between down-regulation and ATL development (OR, 0.8). CONCLUSION: HTLV-1 mono-infection up-regulates the expression of IL-28B transcripts in genotype-dependent manner, whiles HTLV-1/HCV co-infection down-regulates regardless of ATL development.

Nationwide survey of adult T-cell leukemia/lymphoma (ATL) in Japan.

In a nationwide survey of ATL in Japan, a total of 910 cases of ATL and 7,164 cases of B-NHL as a control disease, newly diagnosed from January 2006 to December 2007 (2 years), were enrolled from 156 hospitals. Male-female ratios were 1.16 for ATL and 1.22 for B-NHL. Among all ATL cases registered, 59.8% were from an HTLV-1 endemic area in Kyushu, and the ratio of ATL to B-NHL in this area was 1 to 3, while that in a non-endemic area in Tokyo was 1 to 40. Compared to previous nationwide studies, the age of ATL patients shifted toward older ages and the mean age gradually increased from 52.7 years in the first survey (cases before 1980) to 61.1 years in the ninth survey (1996-1997) and, finally, to 66.0 years in the present study (range: 19 to 94, median: 67). On subtype classification, 46.7% were classified as the acute type, 34.8% the lymphoma type, 10.3% the smoldering type, and 8.2% the chronic type, and the rate of the acute type decreased with an increase in the lymphoma type compared to that in previous studies. An increase in the mean age is explained by the high HTLV-1 prevalence in elderly people over 64 years old in endemic areas (20%), and by the continual development of ATL from this large pool of HTLV-1 carriers. According to mortality statistics from the Ministry of Health, Labor and Welfare in Japan, approximately 1,000 people die annually from ATL, a statistic that has not changed at least for the past decade.

Advantage of higher-avidity CTL specific for Tax against human T-lymphotropic virus-1 infected cells and tumors.

Strong CTL response can be observed and associated with the control of proviral load in human T-lymphotropic virus type 1 (HTLV-1) infection. However, there are few details with regard to how HTLV-1 specific CTLs work against HTLV-1 infected cells and adult T-cell leukemia cells (ATLs). In this study, using Tax-specific CTL lines with high- and low-functional avidity developed from HLA-A2-transgenic mice, we showed that higher avidity CTLs specific for Tax expressing larger numbers of TCRs and better binding strength to the antigen-HLA-A2 complex are much more efficient at eliminating HTLV-1 infected cells and, in particular, ATL tumor cells with the ability of recognizing a latent level of Tax product detected only with a real-time PCR. These findings suggest that such higher avidity CTLs specific for Tax in HTLV-1 could be responsible for preventing the development of HTLV-1 infection by detecting trace amount of antigens.

Aberrant overexpression of membrane-associated mucin contributes to tumor progression in adult T-cell leukemia/lymphoma cells.

Aberrant overexpression of membrane-associated mucin (MUC1) is implicated in the pathogenesis of cancer, particularly of adenocarcinomas. Adult T-cell leukemia/lymphoma (ATL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), exhibits invasive tropism into various organs, resulting in disease progression and resistance to treatment. In the present study, we showed that MUC1 is overexpressed exclusively in cells of ATL among hematological malignancies. Furthermore, increased expression of MUC1 correlated with a poor prognosis, suggesting MUC1 to be a prognostic marker in ATL. Various functional analyses with knockdown experiments using a specific siRNA for MUC1 revealed that MUC1 is involved in cell growth, cell aggregation, and resistance to apoptosis. Although it has been shown that the anti-adhesive properties of MUC1 facilitate migration and metastasis of tumor cells, our findings indicated that MUC1 contributes to cell-cell adhesion. Mucins thus seem to play a role in the pathogenesis and/or progression of ATL.

c-Maf suppresses human T-cell leukemia virus type 1 Tax by competing for CREB-binding protein.

Latent infection of human T-cell leukemia virus type 1 (HTLV-1) is considered to be preferentially associated with CCR4(+) CD4(+) T cells. Here we report that c-Maf, one of the critical transcription factors for Th2 differentiation, suppresses the transcriptional activity of HTLV-1 Tax by competing for CREB-binding protein. Notably, c-maf expression is selectively induced in a fraction of CCR4(+) CD4(+) T cells upon activation. Furthermore, c-Maf significantly decreases Tax-induced HTLV-1 envelope gp46 gene expression from an infectious HTLV-1 molecular clone and tax expression in a cell-free HTLV-1 infection system. Collectively, c-Maf may play a role in latent infection of HTLV-1 in CCR4(+) CD4(+) T cells by negatively regulating Tax activity.

Overexpression of Enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy.

BACKGROUND: Enhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression. DESIGN AND METHODS: In this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance. RESULTS: Significantly higher levels of Enhancer of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4(+) T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cells. CONCLUSIONS: These findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.

In vivo efficacy of doripenem (DRPM) against Pseudomonas aeruginosa in murine chronic respiratory tract infection model.

Doripenem is a carbapenem antibiotic with broad-spectrum coverage of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, and is considered to be as effective as meropenem. The in vivo activity of doripenem was thus compared with that of meropenem in a chronic lower respiratory P. aeruginosa infection mouse model. The number of viable bacteria in the lungs of mice after treatment with doripenem, meropenem, and saline was 2.01 ± 0.69, 2.03 ± 0.48, and 3.90 ± 1.40 log10 CFU/lung, respectively. The number of viable bacteria in the lungs of mice treated with doripenem and meropenem was significantly lower than that in lungs of controls. Histopathological examination of lung specimens from the control group revealed promotion of the inflammatory response in chronic bronchial infection. However, the groups treated with doripenem and meropenem showed weaker inflammatory responses. These results suggest that doripenem treatment is effective against chronic airway infection with P. aeruginosa.

Legionella pneumophila induces cathepsin B-dependent necrotic cell death with releasing high mobility group box1 in macrophages.

BACKGROUND: Legionella pneumophila (LPN) can cause a lethal infectious disease with a marked inflammatory response in humans. However, the mechanism of this severe inflammation remains poorly understood. Since necrosis is known to induce inflammation, we investigated whether LPN induces necrosis in macrophages. We also analyzed the involvement of lysosomal cathepsin B in LPN-induced cell death. METHODS: The human monocytic cell line THP-1 was infected with LPN, NUL1 strain. MG132-treated cells were used as apoptotic control cells. After infection, the type of cell death was analyzed by using microscopy, LDH release and flow cytometry. As a proinflammatory mediator, high-mobility group box 1 (HMGB-1), was measured. Cathepsin B activity was also measured and the inhibitory effects of cathepsin B on LPN-induced cell death were analyzed. RESULTS: THP-1 cells after treatment with high dose of LPN showed necrotic features with releasing HMGB-1. This necrosis and the HMGB-1 release were inhibited by a specific lysosomal cathepsin B inhibitor and were characterized by a rapid and high activation of cathepsin B that was not observed in apoptotic control cells. The necrosis was also accompanied by cathepsin B-dependent poly(ADP-ribose) polymerase (PARP) cleavage. CONCLUSIONS: We demonstrate here that L. pneumophila rapidly induces cathepsin B-dependent necrosis in a dose-dependent manner and releases a proinflammatory mediator, HMGB-1, from macrophages. This report describes a novel aspect of the pathogenesis of Legionnaires' disease and provides a possible therapeutic target for the regulation of inflammation.

In vivo efficacy of sivelestat in combination with pazufloxacin against Legionella pneumonia.

It is important to regulate excessive inflammation when patients with severe infectious disease are treated. Sivelestat sodium hydrate (sivelestat), a neutrophil elastase inhibitor, is used in the treatment of lung injury but its effect on bacterial pneumonia is unknown. The authors examined the efficacy of sivelestat in combination with a fluoroquinolone in a Legionella pneumophila pneumonia mouse model. The combination therapy did not show a significant survival improvement compared to the treatment with fluoroquinolone alone, but reduced bacteria number and inflammatory cells in the early phase. The combination therapy can contribute to treatment of L. pneumophila pneumonia with protecting lungs.

Azithromycin inhibits nontypeable Haemophilus influenzae-induced MUC5AC expression and secretion via inhibition of activator protein-1 in human airway epithelial cells.

Nontypeable Haemophilus influenzae (NTHi) is one of the most common pathogens in chronic airway infections and exacerbation. The hallmark of chronic respiratory diseases, including cystic fibrosis, diffuse panbronchiolitis and chronic obstructive pulmonary disease, is mucin overproduction. Prolonged macrolide antibiotic therapy at low doses is known to improve clinical outcome in patients with chronic respiratory diseases via anti-inflammatory effects. In this study, we investigated the effects of macrolide therapy on NTHi-induction of the MUC5AC mucin in human airway epithelial cells. A 15-membered macrolide, azithromycin, but not a 14-membered macrolide, clarithromycin, inhibited NTHi-induction of MUC5AC at both the mRNA and protein levels through selective suppression of activation of the transcription factor activator protein-1. Our findings suggest that each macrolide affects MUC5AC production in different ways and that azithromycin is more suitable for the treatment of NTHi-induced respiratory infection.

High human T cell leukemia virus type-1(HTLV-1) provirus load in patients with HTLV-1 carriers complicated with HTLV-1-unrelated disorders.

BACKGROUND: To address the clinical and virological significance of a high HTLV-1 proviral load (VL) in practical blood samples from asymptomatic and symptomatic carriers, we simultaneously examined VL and clonal expansion status using polymerase chain reaction (PCR) quantification (infected cell % of peripheral mononuclear cells) and Southern blotting hybridization (SBH) methods. RESULTS: The present study disclosed extremely high VL with highly dense smears with or without oligoclonal bands in SBH. A high VL of 10% or more was observed in 16 (43.2%) of a total of 33 samples (one of 13 asymptomatic carriers, 8 of 12 symptomatic carriers, and 7 of 8 patients with lymphoma-type ATL without circulating ATL cells). In particular, an extremely high VL of 50% or more was limited to symptomatic carriers whose band findings always contained at least dense smears derived from polyclonally expanded cells infected with HTLV-1. Sequential samples revealed that the VL value was synchronized with the presence or absence of dense smears, and declined at the same time as disappearing dense smears. Dense smears transiently emerged at the active stage of the underlying disease. After disappearance of the smears, several clonal bands became visible and were persistently retained, explaining the process by which the clonality of HTLV-1-infected cells is established. The cases with only oligoclonal bands tended to maintain a stable VL of around 20% for a long time. Two of such cases developed ATL 4 and 3.5 years later, suggesting that a high VL with oligoclonal bands may be a predisposing risk to ATL. CONCLUSION: The main contributor to extremely high VL seems to be transient emergence of dense smears detected by the sensitivity level of SBH, corresponding to polyclonal expansion of HTLV-1-infected cells including abundant small clones. Major clones retained after disappearance of dense smears stably persist and acquire various malignant characteristics step by step.

Long-term study of indolent adult T-cell leukemia-lymphoma.

The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.

Genetic diagnosis of community-acquired MRSA: a multiplex real-time PCR method for Staphylococcal cassette chromosome mec typing and detecting toxin genes.

Methicillin-resistant Staphylococcus aureus (MRSA) causes a wide range of infections in health care settings and community environments. In particular, community-acquired MRSA (CA-MRSA) is important for clinicians because many fatal cases in healthy populations have been reported. Staphylococcal cassette chromosome mec (SCCmec) is a mobile genetic element and carries the central determinant for broad-spectrum beta-lactam resistance encoded by the mecA gene. The emergence of MRSA is due to the acquisition and insertion of the SCCmec element into the chromosome. CA-MRSA is characterized as SCCmec type IV. Thus, we aimed to establish a novel multiplex real-time PCR method to distinguish SCCmec type, which enables us to evaluate the pathogenicity of MRSA. A total of 778 MRSA were isolated at Nagasaki University Hospital from 2000 to 2007. All isolates were subjected to minimal inhibitory concentration testing and PCR for SCCmec typing and detecting genes of toxins: tst (toxic shock syndrome toxin 1), sec (encoded enterotoxin type c), etb (exfoliative toxin type b), and lukS/F-PV (Panton-Valentine leukocidin). PCR was performed to amplify a total of 10 genes in the same run. The 667 MRSA clones detected from pus in 778 clones were classified as SCCmec type II (77.7%), type IV (19.2%), and type I (3.0%). 87.5% of SCCmec type II clone had tst and sec genes. No isolate was lukS/F-PV positive. The present study indicates the high rate of lukS/F-PV-negative SCCmec type IV in Nagasaki. Our PCR method is convenient for typing MRSA and detecting toxins in Japan.

Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

PURPOSE: KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design. RESULTS: Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses. CONCLUSION: KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.

Trends in HTLV-1 prevalence and incidence of adult T-cell leukemia/lymphoma in Nagasaki, Japan.

Most previous studies aimed at estimating the number of human T-cell leukemia virus type-1 (HTLV-1) carriers in endemic areas have been based on seroprevalence rates in blood donors; however, this may result in underestimation because of the healthy donor effect. People who have health problem do not donate blood. In the present study, the number of HTLV-1 carriers in Nagasaki City was estimated based on the seroprevalence rates in a hospital-based population from Nagasaki University Hospital. In accordance with previous reports, seroprevalence of HTLV-1 was higher in females, and year of birth-specific seroprevalence showed a significant annual decline in both genders (P for trend: <0.0001). The estimated number of HTLV-1 carriers in Nagasaki City was 36,983. The incidence of adult T-cell leukemia/lymphoma (ATLL) among HTLV-1 carriers was estimated using data from the Nagasaki Prefectural Cancer Registry. The estimated annual incidence of ATLL was 61 per 100,000 HTLV-1 carriers, and the crude lifetime risk of the development was 7.29% for males and 3.78% for females. There is a large pool of HTLV-1 carriers aged over 70 years, and a continuing development of cases of ATLL among the elderly is therefore expected.

Overexpression of caveolin-1 in adult T-cell leukemia.

Caveolin-1 is implicated in the regulation of signal pathways. Adult T-cell leukemia (ATL) is a T-cell malignancy causatively associated with human T-cell leukemia virus type 1 (HTLV-1). To determine the role of caveolin-1 in leukemogenesis, we examined caveolin-1 expression levels in HTLV-1-infected T-cell lines and ATL cells. These cells expressed high levels of caveolin-1 compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Caveolin-1-positive ATL cells were detected in ATL lymph nodes and skin lesions, and caveolin-1 was also detected in the plasma of patients with ATL. Infection of a human T-cell line, an epithelial cell line, and normal PBMCs with HTLV-1 induced caveolin-1 expression. The viral protein Tax transcriptionally activated caveolin-1 gene through nuclear factor-kappaB and cAMP response element binding protein signal pathways. HTLV-1-infected T-cell lines, and ATL cells are known to be resistant to transforming growth factor beta (TGF-beta)-induced growth inhibition. Caveolin-1 was colocalized with TGF-beta type I receptor in HTLV-1-infected T-cell lines and suppressed TGF-beta signaling. Caveolin-1 knockdown in an HTLV-1-infected T-cell line exhibited susceptibility to TGF-beta. Thus, we describe a new function for Tax, repression of TGF-beta signaling through caveolin-1 expression, which may play a critical role in ATL leukemogenesis.

Multiple immune abnormalities in a patient with idiopathic CD4+ T-lymphocytopenia.

Idiopathic CD4+ T-lymphocytopenia (ICL) is a new disease entity characterized by CD4+ T-lymphocyte depletion without evidence of HIV infection. We report a 27-year-old ICL patient with a long history of multiple immune abnormalities. His CD4+ T-lymphocyte count started to decrease after generalized lymphadenopathy of an unknown cause at age 3. He satisfied the criteria for ICL at age 9, and the decreased CD4+ T-lymphocyte count persisted for more than 18 years. This is probably the first childhood-onset ICL case in which the trigger event for the development was known together with the patient's autoimmune background.