Age‐ and sex‐specific cumulative rate and risk of ATLL for HTLV‐I carriers

Kondo, Toshifumi; Kono, Hidehisa; Miyamoto, Naoaki; Yoshida, Ryouichi; Toki, H; Matsumoto, Isao; Hara, Masamichi; Inoue, Hiroo; Inatsuki, Akira; Funatsu, Takashi; Yamano, Norio; Bando, Fumihiro; Iwao, Eiichi; Miyoshi, Isao; Hinuma, Yorio; Hanaoka, Masao

doi:10.1002/ijc.2910430618

Cited by 104 publications

(54 citation statements)

References 10 publications

(16 reference statements)

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“…Infection early in life is associated with the development of ATL and the estimated lifetime risk is about 5% in individuals infected before the age of 20 years (Cleghorn et al, 1995;Wilks et al, 1996). The incidence rate is 2-4 per 100 000 person-years and males have higher risk than females (Kondo et al, 1989;Cleghorn et al, 1995). The clinical features, treatment and prevention of ATL are reviewed in this volume.…”

Section: Adult T-cell Leukemia/lymphomamentioning

confidence: 99%

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

2005

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Over the past 25 years, animal models of human T-lymphotropic virus type 1 (HTLV-1) infection and transformation have provided critical knowledge about viral and host factors in adult T-cell leukemia/lymphoma (ATL). The virus consistently infects rabbits, some non-human primates, and to a lesser extent rats. In addition to providing fundamental concepts in viral transmission and immune responses against HTLV-1 infection, these models have provided new information about the role of viral proteins in carcinogenesis. Mice and rats, in particular immunodeficient strains, are useful models to assess immunologic parameters mediating tumor outgrowth and therapeutic invention strategies against lymphoma. Genetically altered mice including both transgenic and knockout mice offer important models to test the role of specific viral and host genes in the development of HTLV-1-associated lymphoma. Novel approaches in genetic manipulation of both HTLV-1 and animal models are available to address the complex questions that remain about viral-mediated mechanisms of cell transformation and disease. Current progress in the understanding of the molecular events of HTLV-1 infection and transformation suggests that answers to these questions are approachable using animal models of HTLV-1-associated lymphoma Oncogene (2005) 24, 6005-6015.

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Section: Adult T-cell Leukemia/lymphomamentioning

confidence: 99%

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

2005

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“…[1][2][3] Although the majority of HTLV-1-infected individuals remain asymptomatic throughout their lives, approximately 5% of HTLV-1 carriers develop ATL or HAM/TSP following a long latency period. 4 In addition to the classic structural proteins required for retroviral replication, the HTLV-1 proviral genome encodes several accessory and regulatory proteins, including the viral transcriptional activator Tax and the HTLV-1 bZIP factor (HBZ), which are thought to be linked to HTLV-1 pathogenesis. 5,6 ATL is an aggressive malignancy of mature CD4 T cells, characterized by frequent visceral involvement, lymphadenopathy, hypercalcemia or hypercytokinemia, and monoclonal proliferation of HTLV-1-infected tumor cells.…”

Section: Introductionmentioning

confidence: 99%

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

Tezuka

Xun

Tei

et al. 2014

Blood

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Key Points• Humanized mice, IBMIhuNOG, were generated by intra-bone marrow injection of human CD1331 hematopoietic stem cells.• HTLV-1-infected IBMIhuNOG mice recapitulated distinct ATL-like symptoms as well as HTLV-1-specific adaptive immune responses.Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis. To elucidate ATL pathogenesis in vivo, a variety of animal models have been established; however, the mechanisms driving this disorder remain poorly understood due to deficiencies in each of these animal models. Here, we report a novel HTLV-1-infected humanized mouse model generated by intra-bone marrow injection of human CD133 1 stem cells into NOD/Shi-scid/IL-2Rgc null (NOG) mice (IBMI-huNOG mice).Upon infection, the number of CD4 1 human T cells in the periphery increased rapidly, and atypical lymphocytes with lobulated nuclei resembling ATL-specific flower cells were observed 4 to 5 months after infection. Proliferation was seen in both CD25 2 and CD25 1 CD4 T cells with identical proviral integration sites; however, a limited number of CD25 1 -infected T-cell clones eventually dominated, indicating an association between clonal selection of infected T cells and expression of CD25. Additionally, HTLV-1-specific adaptive immune responses were induced in infected mice and might be involved in the control of HTLV-1-infected cells. Thus, the HTLV-1-infected IBMI-huNOG mouse model successfully recapitulated the development of ATL and may serve as an important tool for investigating in vivo mechanisms of ATL leukemogenesis and evaluating anti-ATL drug and vaccine candidates. (Blood. 2014;123(3):346-355)

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“…Although the majority of HTLV-1-infected individuals remain asymptomatic during their lifetimes, a few percent of HTLV-1 carriers develop ATL after a long latency period (25,45). HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/ TSP), a chronic progressive neuromyelopathy, and other HTLV-1-related diseases are also associated with HTLV-1 infection (4,19,35).…”

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confidence: 99%

Expansion of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Reservoir in Orally Infected Rats: Inverse Correlation with HTLV-1-Specific Cellular Immune Response

Hasegawa

Ohashi

Hanabuchi

et al. 2003

J Virol

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Adult T-cell leukemia (ATL) occurs in a small population of human T-cell leukemia virus type 1 (HTLV-1)-infected individuals. Although the critical risk factor for ATL development is not clear, it has been noted that ATL is incidentally associated with mother-to-child infection, elevated proviral loads, and weakness in HTLV-1-specific T-cell immune responses. In the present study, using a rat system, we investigated the relationships among the following conditions: primary HTLV-1 infection, a persistent HTLV-1 load, and host HTLV-1-specific immunity. We found that the persistent HTLV-1 load in orally infected rats was significantly greater than that in intraperitoneally infected rats. Even after inoculation with only 50 infected cells, a persistent viral load built up to considerable levels in some orally infected rats but not in intraperitoneally infected rats. In contrast, HTLV-1-specific cellular immune responses were markedly impaired in orally infected rats. As a result, a persistent viral load was inversely correlated with levels of virus-specific T-cell responses in these rats. Otherwise very weak HTLV-1-specific cellular immune responses in orally infected rats were markedly augmented after subcutaneous reimmunization with infected syngeneic rat cells. These findings suggest that HTLV-1-specific immune unresponsiveness associated with oral HTLV-1 infection may be a potential risk factor for development of ATL, allowing expansion of the infected cell reservoir in vivo, but could be overcome with immunological strategies.Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis (9,38,41). Although the majority of HTLV-1-infected individuals remain asymptomatic during their lifetimes, a few percent of HTLV-1 carriers develop ATL after a long latency period (25, 45). HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/ TSP), a chronic progressive neuromyelopathy, and other HTLV-1-related diseases are also associated with HTLV-1 infection (4,19,35). Genetic differences among HTLV-1 strains are not associated with the clinical outcomes of HTLV-1 infection (2,23,24).In cohort studies of HTLV-1 carriers, it appeared that risk factors for ATL may include vertical HTLV-1 infection, gender (male Ͼ female), an increase in the number of abnormal lymphocytes that is associated with an increase in the HTLV-1 proviral load, and a low anti-Tax antibody level in serum (10-12). Genetic analysis indicated that ATL and HAM/TSP patients in an area of endemicity show significant segregation of HLA haplotypes (42). These observations indicate that the pathogenesis of HTLV-1 is more likely to be influenced by host factors.Immunological studies have found a clear difference in HTLV-1-specific T-cell immune responses among HTLV-1-related diseases. HTLV-1-specific cytotoxic T lymphocytes (CTLs) are highly activated in HAM/TSP patients and can also be induced in asymptomatic carriers but only rarely in ATL patients (13,15,1...

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Age‐ and sex‐specific cumulative rate and risk of ATLL for HTLV‐I carriers

Cited by 104 publications

References 10 publications

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

Expansion of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Reservoir in Orally Infected Rats: Inverse Correlation with HTLV-1-Specific Cellular Immune Response

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