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Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) in infected individuals

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...

Background: Dietary supplementation with lactic acid bacteria (LAB) is a potential approach to the prevention and manipulation of allergic diseases such as atopic dermatitis (AD). However, the influence of different bacterial strains and their immunomodulating capacities is still largely unknown. Methods: AD-like skin lesions were induced by sensitization to and repeated challenges with picrylchloride in the Th2-skewed NC/Nga mouse strain. The effects of LAB supplementation were assessed over time by monitoring clinical scores and plasma IgE levels. In some cases, mast cell infiltration, cutaneous hypersensitivity responses and cytokine mRNA expression in auricles were also examined. Additionally, cytokine production in vitro and cytokine mRNA accumulation in major lymphoid tissues were measured, comparing Lactobacillus paracasei KW3110 with L. rhamnosus GG (LGG). Results: Supplementation with KW3110 significantly reduced the development of AD-like skin lesions, accompanied by less mast cell infiltration and lower plasma IgE levels. KW3110 also suppressed immediate hypersensitivity reactions and IL-4 mRNA expression in the auricles. These preventive effects sustained when supplementation was terminated; moreover, inhibitory effects were also observed even when supplementation was initiated after the onset of symptoms. In accordance with its effects on IL-12 and IL-4 production in vitro, KW3110 prevented the emergence of clinical symptoms more effectively than LGG in vivo. Conclusions: Supplementation with KW3110 significantly attenuated the onset and exacerbation of AD-like symptoms in NC/Nga mice. The effects were more prominent than those obtained with LGG, suggesting the importance of differences between LAB strains and their immunomodulating capacity.

Host immunity influences clinical manifestations of human T-cell leukemia virus type 1 (HTLV-1

The major route of human T-cell leukemia virus type 1 (HTLV-1) infection is mother-to-child transmission caused by breast-feeding. We investigated the host immune responses to orally established persistent HTLV-1 infection in adult rats. HTLV-1-producing MT-2 cells were inoculated into immunocompetent adult rats either orally, intravenously, or intraperitoneally. HTLV-1 proviruses were detected in the peripheral blood and several organs for at least 12 weeks. Transmission of HTLV-1 to these animals was confirmed by analysis of HTLV-1 flanking regions. Despite persistent HTLV-1 presence, none of the orally inoculated rats produced detectable levels of anti-HTLV-1 antibodies, whereas all intravenously or intraperitoneally inoculated rats showed significant anti-HTLV-1 antibody responses. T-cell proliferative responses against HTLV-1 were also absent in orally inoculated rats. Our findings suggest that gastrointestinal exposure of adult rats to HTLV-1-infected cells induces persistent HTLV-1 infection in the absence of both humoral and cellular immune responses against HTLV-1. This immune unresponsiveness at primary infection may subsequently affect the host defense ability against HTLV-1.

Human T-cell leukemia virus type 1 (HTLV-1) has been shown to be the etiologic agent of adult T-cell leukemia (ATL), but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to investigate the mechanisms of HTLV-1 leukemogenesis, we developed a rat model system in which ATL-like disease was reproducibly observed, following inoculation of various rat HTLV-1-immortalized cell lines. When previously established cell lines, F344-S1 and TARS-1, but not TART-1 or W7TM-1, were inoculated, systemic multiple tumor development was observed in adult nude (nu/nu) rats. FPM1 cells, newly established from a heterozygous (nu/+) rat syngeneic to nu/nurats, caused transient tumors only at the injection site in adult nu/nu rats, but could progressively grow in newborn nu/nu rats and metastasize in lymph nodes. The derivative cell line (FPM1-V1AX) serially passed through newbornnu/nu rats acquired the potency to grow in adultnu/nu rats. These results indicated that only some with additional changes but not all of the in vitro HTLV-1-immortalized cell lines possessed in vivo tumorigenicity. Using the syngeneic system, we further showed the inhibition of tumor development by transferring splenic T cells from immunized rats, suggesting the involvement of T cells in the regression of tumors. This novel and reproducible nude rat model of human ATL would be useful for investigation of leukemogenesis and antitumor immune responses in HTLV-1 infection.

Human T-cell leukemia virus type 1 (HTLV-1) causes T-cell malignancies in a small percentage of the population infected with the virus after a long carrier state. In the present study, we established a seronegative HTLV-1 carrier state in rats inoculated with a newly established HTLV-1-infected rat T cell line, FPM1. FPM1 originated from rat thymocytes cocultured with a human HTLV-1 producer, MT-2 cells, and expressed rat CD4, CD5, CD25, and HTLV-1 Tax. However, FPM1 scarcely expressed other major HTLV-1 structural proteins and failed to induce typical antibody responses against HTLV-1 in inoculated rats. In contrast, control rats inoculated with MT-2 cells generated significant levels of anti-HTLV-1 antibodies. HTLV-1 proviruses were detected in peripheral blood cells of syngeneic rats inoculated with FPM1 for more than 1 year. Analysis of the flanking region of HTLV-1 provirus integrated into host cells suggested that FPM1 cells remained in these animals over a relatively long period of time. However, a similar seronegative HTLV-1 carrier state was induced in the rats inoculated with mitomycin C-treated FPM1 cells and also in FPM1-inoculated allogeneic rats, suggesting that FPM1 could also transmit HTLV-1 into host cells in vivo. Our findings indicated that (i) HTLV-1-immortalized T cells which preferentially express HTLV-1 Tax persisted in vivo but failed to induce any diseases in immunocompetent syngeneic rats and that (ii) suboptimal levels of HTLV-1 for antibody responses allowed the establishment of persistent HTLV-1 infection.