RESUMEN
Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Virus Linfotrópico T Tipo 1 Humano , Neopterin , Paraparesia Espástica Tropical , Humanos , Método Doble Ciego , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/líquido cefalorraquídeo , Adulto , Anciano , Neopterin/líquido cefalorraquídeo , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Quimiocina CXCL10/líquido cefalorraquídeo , Carga Viral/efectos de los fármacos , Resultado del TratamientoRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1) can cause HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Current treatment options for HAM/TSP are limited. We present a woman with rapidly-progressive HAM/TSP with significant, sustained clinical improvement following initiation of mycophenolate mofetil (MMA). Peripheral blood mononuclear cells from the patient, her asymptomatic carrier husband and eight healthy controls were isolated. Frequencies of T-cell populations upon exposure to low and high MMA concentrations and differences in proliferation were analyzed using flow cytometry and a CSFE-proliferation assay. Characterization of T-cell function and proliferation showed higher levels of GranzymeB in HTLV-1+ donors. The improvement and stability of symptoms in this patient with HAM/TSP following MMA initiation requires further study as a potential treatment for HAM/TSP.
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Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Humanos , Femenino , Virus Linfotrópico T Tipo 1 Humano/fisiología , Ácido Micofenólico/uso terapéutico , Leucocitos Mononucleares , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/diagnósticoRESUMEN
BACKGROUND: Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date. CASE PRESENTATION: A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment. CONCLUSION: This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.
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Enfermedades de la Médula Ósea , Infecciones por VIH , Virus Linfotrópico T Tipo 1 Humano , Miopatías Nemalínicas , Paraparesia Espástica Tropical , Humanos , Adulto , Femenino , Anciano , Paraparesia Espástica Tropical/complicaciones , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/tratamiento farmacológico , Miopatías Nemalínicas/complicaciones , Infecciones por VIH/complicaciones , Fibras Musculares Esqueléticas/patología , Enfermedades de la Médula Ósea/complicacionesRESUMEN
BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurological condition characterized by progressive myelopathic symptoms including spasticity, pain, weakness, and urinary symptoms, without proven treatments. Mogamulizumab (MOG) is a monoclonal antibody that binds CCR4 and leads to the clearance of HTLV-1-infected CCR4+ cells. A phase 1-2a study in Japan evaluated MOG for the treatment of HAM/TSP and reported decreases in HTLV-1 proviral load and neuroinflammatory markers, with clinical improvement in some participants. METHODS: We administered MOG 0.1 mg/kg every 8 weeks to individuals with HAM/TSP as a compassionate and palliative treatment. Patients who received MOG had (1) a positive peripheral HTLV-1 antibody, (2) progressive myelopathic symptoms, and (3) a diagnosis of HAM/TSP. RESULTS: Four female patients, ages 45-68, received MOG (range, 2-6 infusions) between 1 November 2019 and 30 November 2022. Two patients with <3 years of symptoms had milder disease, with Osame scores <4. The other 2, with >7 years of symptoms, had Osame scores >5. One patient, with 6 total treatments, received dose-reduced MOG after she developed a rash at the initial dose. The 2 patients with milder baseline disease reported symptomatic improvement and saw reductions in Osame and/or modified Ashworth scale scores during follow-up. The other 2 patients showed no improvement. All 4 developed rashes after receiving MOG-a treatment-limiting event in some cases. CONCLUSIONS: Clinical trials are needed including diverse patient populations to assess the potential role of MOG for HAM/TSP. Our findings may help inform the development of these trials.
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Exantema , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Humanos , Femenino , Paraparesia Espástica Tropical/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Carga ViralRESUMEN
Some carriers of human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Current treatments for HAM/TSP are insufficient with problematic long-term side effects. This study evaluated the long-term safety and efficacy of the anti-CCR4 antibody mogamulizumab in patients with HAM/TSP over a 4-year period. We conducted an open-label, extended long-term study (UMIN trial number: UMIN000019942) of a phase 1-2a trial with mogamulizumab for HAM/TSP (UMIN000012655). The study participants were patients with corticosteroid-resistant HAM/TSP who could walk 10 m with or without assistive tools. Mogamulizumab was administered at 0.01, 0.03, 0.1 or 0.3 mg/kg at intervals of ≥8 weeks (0.01 and 0.03 mg/kg) or ≥12 weeks (0.1 and 0.3 mg/kg). HTLV-1 proviral load, CSF inflammatory markers and clinical symptoms were summarized by descriptive statistics. Missing observations were imputed using the last-observation-carried-forward method. As a post hoc analysis, we evaluated the therapeutic effect of mogamulizumab on gait function by comparing it with contemporary control data from a HAM/TSP patient registry. Of the 21 participants in the phase 1-2a, 18 (86%) enrolled in the long-term study and 15 (71%) continued repeated doses of mogamulizumab for 4 years. The median dose was 0.1 mg/kg after 4 years. Seventeen of 21 participants (81%) experienced grade 1-2 skin-related adverse events. Observed grade 3 drug-related adverse effects included three cases of lymphopenia and one case each of microscopic polyangiitis, elevated levels of aspartate aminotransferase, and neutropenia. Four of 21 participants (19%) developed neutralizing antibodies. After 4 years, the peripheral blood proviral load and the number of infected cells in CSF decreased by 60.7% and 66.3%, respectively. Neopterin and CXCL10 CSF concentrations decreased by 37.0% and 31.0%, respectively. Among the 18 participants, spasticity and Osame Motor Disability Score (OMDS) improved in 17 (94%) and four (22%), respectively. However, 10 m walking time worsened by 7.3% on average. Comparison with the contemporary control group demonstrated that mogamulizumab inhibited OMDS progression (P = 0.02). The results of the study suggest that mogamulizumab has long-term safety and inhibitory effects on lower limb motor disability progression in corticosteroid-treated patients with HAM/TSP. This will provide a basis for the application of mogamulizumab in HAM/TSP treatment.
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Personas con Discapacidad , Virus Linfotrópico T Tipo 1 Humano , Trastornos Motores , Paraparesia Espástica Tropical , Humanos , Paraparesia Espástica Tropical/tratamiento farmacológicoRESUMEN
The human T cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that persists as a provirus in the genome of infected cells and can lead to adult T cell leukemia (ATL). Worldwide, more than 10 million people are infected and approximately 5% of these individuals will develop ATL, a highly aggressive cancer that is currently incurable. In the last years, genome editing tools have emerged as promising antiviral agents. In this proof-of-concept study, we use substrate-linked directed evolution (SLiDE) to engineer Cre-derived site-specific recombinases to excise the HTLV-1 proviral genome from infected cells. We identified a conserved loxP-like sequence (loxHTLV) present in the long terminal repeats of the majority of virus isolates. After 181 cycles of SLiDE, we isolated a designer-recombinase (designated RecHTLV), which efficiently recombines the loxHTLV sequence in bacteria and human cells with high specificity. Expression of RecHTLV in human Jurkat T cells resulted in antiviral activity when challenged with an HTLV-1 infection. Moreover, expression of RecHTLV in chronically infected SP cells led to the excision of HTLV-1 proviral DNA. Our data suggest that recombinase-mediated excision of the HTLV-1 provirus represents a promising approach to reduce proviral load in HTLV-1-infected individuals, potentially preventing the development of HTLV-1-associated diseases.
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/genética , Provirus/genética , AntiviralesRESUMEN
OBJECTIVE: HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP. METHODS: This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability. RESULTS: The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly. INTERPRETATION: l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP. TRIAL REGISTRATION NUMBER: UMIN000023854.
Asunto(s)
Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Humanos , Femenino , Anciano , Masculino , Equilibrio Postural , Estudios de Tiempo y Movimiento , Paraparesia Espástica Tropical/tratamiento farmacológicoRESUMEN
Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).
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Corticoesteroides/uso terapéutico , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical/tratamiento farmacológico , Anciano , Personas con Discapacidad , Femenino , Humanos , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Trastornos Motores/tratamiento farmacológico , Paraparesia Espástica Tropical/líquido cefalorraquídeo , Prednisolona/uso terapéutico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
RATIONALE: Adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-1, but the coexistence of both disorders is rare. The estimated incidence is approximately 3%. PATIENT CONCERNS: A 54-year-old man was unable to stand up because of spastic paraparesis 1 month after the onset. He developed lymphadenopathy in the left supraclavicular fossa 5 months after the onset. The spastic paraplegia and sensory symptoms below the thoracic spinal cord level worsened. DIAGNOSES: Both blood and cerebrospinal fluid (CSF) tests were positive for anti-HTLV-1 antibodies. The patient was diagnosed with rapidly progressive HAM/TSP. He was also diagnosed with lymphoma-type ATL by the biopsy specimen of the lymph node. CSF examination at the time of symptom exacerbation showed abnormal lymphocytes, suggesting central infiltration of the ATL in the central nervous system. INTERVENTIONS: Methylprednisolone pulse therapy and oral prednisolone maintenance therapy were administered for rapidly progressive HAM/TSP. Intrathecal injection of methotrexate was administered for the suggested central infiltration of the ATL. OUTCOMES: Methylprednisolone pulse therapy and intrathecal injection of methotrexate did not improve the patient's exacerbated symptoms. Five months later, clumsiness and mild muscle weakness of the fingers appeared, and magnetic resonance imaging showed swelling of the cervical spinal cord. Clonality analysis showed monoclonal proliferation only in the DNA of a lymph node lesion, but not in the CSF and peripheral blood cells. LESSONS: This was a case of rapidly progressive HAM/TSP associated with lymphoma-type ATL that was refractory to steroids and chemotherapy. The pathogenesis was presumed to involve ATL cells in the brain and spinal cord because of the presence of abnormal lymphocytes in the CSF, but DNA analysis could not prove direct invasion. This case suggests that when we encounter cases with refractory HAM/TSP, it should be needed to suspect the presence of ATL in the background.
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Leucemia-Linfoma de Células T del Adulto/complicaciones , Paraparesia Espástica Tropical/complicaciones , Femenino , Glucocorticoides/administración & dosificación , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Masculino , Metotrexato/administración & dosificación , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/tratamiento farmacológicoRESUMEN
OBJECTIVE: Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro. Given the substantial clinical experience in human immunodeficiency virus infection and its excellent safety profile, this agent may be an attractive therapeutic option for HAM/TSP patients. METHODS: Sixteen subjects with HAM/TSP received raltegravir 400 mg orally twice daily in an initial 6-month treatment phase, followed by a 9-month post-treatment phase. HTLV-1 PVLs were assessed using droplet digital PCR from the PBMCs every 3 months, and from the CSF at baseline, month 6, and month 15. We also evaluated the ability of raltegravir to regulate abnormal immune responses in HAM/TSP patients. RESULTS: While a downward trend was observed in PBMC and/or CSF PVLs of some patients, raltegravir overall did not have any impact on the PVL in this HAM/TSP patient cohort. Clinically, all patients' neurological scores and objective measurements remained relatively stable, with some expected variability. Immunologic studies showed alterations in the immune profiles of a subset of patients including decreased CD4+ CD25+ T cells and spontaneous lymphoproliferation. INTERPRETATION: Raltegravir was generally well tolerated in this HAM/TSP patient cohort. A subset of patients exhibited a mild decrease in PVL as well as variations in their immune profiles after taking raltegravir. These findings suggest that raltegravir may be a therapeutic option in select HAM/TSP patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT01867320.
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Inhibidores de Integrasa/farmacología , Paraparesia Espástica Tropical/tratamiento farmacológico , Raltegravir Potásico/farmacología , Adulto , Anciano , Femenino , Humanos , Inhibidores de Integrasa/administración & dosificación , Masculino , Persona de Mediana Edad , Proyectos Piloto , Raltegravir Potásico/administración & dosificación , Resultado del TratamientoRESUMEN
Human T-lymphotropic virus type I (HTLV-I) is a retrovirus associated with adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to HAM/TSP and ATL, HTLV-I-associated encephalopathy and cerebellar involvement have been reported. We report a case of an 87-year-old Japanese woman presenting with progressive dysarthria and gait disturbance. Neurological examination showed word-finding difficulty, scanning speech, saccadic eye movements, ocular dysmetria, gaze-evoked nystagmus and bilateral dysmetria. There was no motor weakness or spasticity. HTLV-I antibody was detected in both her serum and cerebrospinal fluid. Cerebrospinal fluid neopterin (57 pg/mL) and IgG index (3.27) were significantly elevated. MRI showed cerebellar swelling. She was finally diagnosed with HTLV-I associated cerebellitis. Two courses of high-dose intravenous methylpredonine therapy attenuated cerebellar ataxia and cerebellar swelling. It suggests that cerebellitis can result from HTLV-I infection, regardless of the existence of ATL or HAM/TSP.
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Ataxia Cerebelosa , Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Nistagmo Patológico , Paraparesia Espástica Tropical , Adulto , Anciano de 80 o más Años , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/etiología , Femenino , Infecciones por HTLV-I/complicaciones , Infecciones por HTLV-I/diagnóstico , Infecciones por HTLV-I/tratamiento farmacológico , Humanos , Paraparesia Espástica Tropical/complicaciones , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/tratamiento farmacológicoRESUMEN
OBJECTIVE: To test the hypothesis that teriflunomide can reduce ex vivo spontaneous proliferation of peripheral blood mononuclear cells (PBMCs) from patients with human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHODS: PBMCs from patients with HAM/TSP were cultured in the presence and absence of teriflunomide and assessed for cell viability, lymphocyte proliferation, activation markers, HTLV-1 tax and HTLV-1 hbz messenger ribonucleic acid (mRNA) expression, and HTLV-1 Tax protein expression. RESULTS: In culture, teriflunomide did not affect cell viability. A concentration-dependent reduction in spontaneous proliferation of PBMCs was observed with 25 µM (38.3% inhibition), 50 µM (65.8% inhibition), and 100 µM (90.7% inhibition) teriflunomide. The inhibitory effects of teriflunomide were detected in both CD8+ and CD4+ T-cell subsets, which are involved in the immune response to HTLV-1 infection and the pathogenesis of HAM/TSP. There was no significant change in HTLV-1 proviral load (PVL) or tax mRNA/Tax protein expression in these short-term cultures, but there was a significant reduction of HTLV-1 PVL due to inhibition of proliferation of CD4+ T cells obtained from a subset of patients with HAM/TSP. CONCLUSIONS: These results suggest that teriflunomide inhibits abnormal T-cell proliferation associated with HTLV-1 infection and may have potential as a therapeutic option in patients with HAM/TSP.
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Crotonatos/farmacología , Hidroxibutiratos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Nitrilos/farmacología , Paraparesia Espástica Tropical/tratamiento farmacológico , Toluidinas/farmacología , Adulto , Anciano , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Productos del Gen tax/metabolismo , Infecciones por HTLV-I/complicaciones , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , ARN Mensajero/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacosRESUMEN
BACKGROUND: HTLV-1 infection causes a chronic, progressive, demyelinating, neuroinflammatory disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Treatment of HAM/TSP patients which have high levels of proviral load and pro-inflammatory markers is a challenge for clinicians. Therefore, we aimed to investigate the immunomodulatory, anti-inflammatory, and antiviral effects of curcumin in HAM/TSP patients. METHODS: In this study, 20 newly diagnosed HAM/TSP patients (2 men and 18 women) were enrolled and evaluated for clinical symptoms, HTLV-1 proviral load, Tax and HBZ expression, neopterin serum concentration, and complete blood count (CBC) before and 12 weeks after treatment with nanomicellar curcumin (80 mg/day, orally). RESULTS: Clinical symptoms such as the mean Osame Motor Disability Score and Ashworth Spasticity Scale Score were significantly improved after the treatment (P = 0.001 and P = 0.001). Sensory symptoms such as pain and paresthesia were significantly decreased in all of the patients (P = 0.001). Furthermore, urinary disorders, including urinary frequency, incontinence, and the feeling of incomplete bladder emptying, were significantly improved (P = 0.001, P = 0.003, and P = 0.03). However, the mean HTLV-1 proviral load (P = 0.97) and CBC were similar, whereas Tax, HBZ, and neopterin levels tend to increase after the treatment (P = 0.004, P = 0.08, and P = 0.04). CONCLUSION: Results suggest that curcumin can safely improve the clinical symptoms of HAM/TSP patients but has no observable positive effects on the HTLV-1 proviral load, Tax, and HBZ expression. Therefore, prolonged use or the use of curcumin with antiviral agents in addition to clinical signs and symptoms can reduce the HTLV-1 proviral load and the expression of functional viral factors such as Tax and HBZ.
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Curcumina , Personas con Discapacidad , Trastornos Motores , Paraparesia Espástica Tropical , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Curcumina/uso terapéutico , Suplementos Dietéticos , Femenino , Humanos , Masculino , Enfermedades Neuroinflamatorias , Paraparesia Espástica Tropical/tratamiento farmacológico , Proteínas de los Retroviridae , Carga ViralRESUMEN
OBJECTIVES: Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA. METHODS: We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method. RESULTS: A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks. CONCLUSION: Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.
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Artritis Reumatoide , Virus Linfotrópico T Tipo 1 Humano , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Humanos , Leucemia-Linfoma de Células T del Adulto , Paraparesia Espástica Tropical/tratamiento farmacológico , Inhibidores del Factor de Necrosis TumoralRESUMEN
Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles of cellular genes in HTLV-1-infected CD4+ T cells await discovery. We performed microarray analysis of CD4+ T cells from HAM/TSP patients and found that the ABL1 is an important gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes and is part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML). ABL1 tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, and dasatinib, are used clinically for treating CML. To evaluate whether ABL1 is indeed important for HAM/TSP, we investigated the effect of TKIs on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKIs. Treating the PBMCs with nilotinib or dasatinib induced significant reductions in PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, ABL1 siRNA transfection reduced cell viability in HTLV-1-infected cell lines, but not in uninfected cell lines. A retrospective survey based on our clinical records found a rare case of HAM/TSP who also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is an important gene for the survival of HTLV-1-infected cells and that TKIs may be potential therapeutic agents for HAM/TSP.
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Infecciones por HTLV-I/complicaciones , Virus Linfotrópico T Tipo 1 Humano/fisiología , Leucocitos Mononucleares/virología , Paraparesia Espástica Tropical/enzimología , Enfermedades de la Médula Espinal/enzimología , Adulto , Anciano , ADN Viral/genética , Femenino , Infecciones por HTLV-I/virología , Humanos , Masculino , Persona de Mediana Edad , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/etiología , Paraparesia Espástica Tropical/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/metabolismo , Provirus/genética , Provirus/fisiología , Estudios Retrospectivos , Enfermedades de la Médula Espinal/tratamiento farmacológico , Enfermedades de la Médula Espinal/etiología , Enfermedades de la Médula Espinal/genética , Carga ViralRESUMEN
Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4+ T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8+ cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.
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Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Leucemia-Linfoma de Células T del Adulto/inmunología , Paraparesia Espástica Tropical/inmunología , Incontinencia Urinaria/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno/inmunología , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Virus Linfotrópico T Tipo 1 Humano/inmunología , Humanos , Inmunidad Celular/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/virología , Activación de Linfocitos/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Neuronas/virología , Fármacos Neuroprotectores/uso terapéutico , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/patología , Paraparesia Espástica Tropical/virología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/virología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virología , Incontinencia Urinaria/tratamiento farmacológico , Incontinencia Urinaria/patología , Incontinencia Urinaria/virologíaAsunto(s)
Quimiocina CXCL10/líquido cefalorraquídeo , Virus Linfotrópico T Tipo 1 Humano , Neopterin/líquido cefalorraquídeo , Paraparesia Espástica Tropical/líquido cefalorraquídeo , Paraparesia Espástica Tropical/tratamiento farmacológico , Prednisolona/uso terapéutico , Biomarcadores/líquido cefalorraquídeo , Glucocorticoides/uso terapéutico , Humanos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) disease is a chronic neuroinflammatory disease, which is associated with HTLV-1 infection. There is no effective and satisfactory treatment of HAM/TSP. It has been shown that curcumin exhibits modulatory effects on apoptosis and cytotoxicity-related molecules in HAM/TSP patients. In the present study, we examined the effect of curcumin on the gene expression of caspase-8, caspase-10, and anti-apoptotic protein c-FLIP, in HAM/TSP patients. Furthermore, we compared the expression of these molecules between HAM/TSP and asymptomatic carriers. Real-time PCR was performed to examine the mRNA expression of caspase-8, caspase-10, and c-FLIP in studied groups. The mRNA expression of caspase-8 and caspase-10 was similar before and after curcumin treatment in HAM/TSP patients (P > 0.05). The mRNA expression of c-FLIPL and c-FLIPs was higher after curcumin treatment compared with before treatment and significant differences were observed between the two groups (P = 0.004 and P = 0.044, respectively). The mRNA expression levels of caspase-8, caspase-10, c-FLIPL, and c-FLIPs were not statistically significant between HAM/TSP patients and asymptomatic carriers (P < 0.05). In conclusion, our results showed that curcumin increased the expression of c-FLIP in HAM/TSP patients which might suggest that, this molecule is involved in the apoptosis of HTLV-1-infected cells. Further studies with large sample size could be useful to clarify the role of this supplement in HAM/TSP patients.
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Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Curcumina/administración & dosificación , Infecciones por HTLV-I/tratamiento farmacológico , Paraparesia Espástica Tropical/tratamiento farmacológico , Curcumina/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Infecciones por HTLV-I/genética , Humanos , Masculino , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/virología , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
The human T-lymphotropic virus type 1 (HTLV-1) is a RNA retrovirus that infects a minimum of 5-10 million people worldwide. Transmission by cell-containing blood products and solid organ transplantation has been reported. Clinical disease occurs in about 5-10% of infected individuals and consists mainly in adult T cell leukemia and HTLV-1-associated myelopathy (HAM). We present a 54-year-old woman who underwent kidney transplant from cadaveric donor in March 2015. Donor also underwent cornea extraction for another recipient (corneal transplant protocol includes HTLV-1/2 serology). Twenty-four hours after completion of kidney transplant donor, HTLV-1 serology was revealed positive. Following experts' recommendations, once donor seropositivity was demonstrated, antiviral prophylaxis including zidovudine and raltegravir was initially given to our patient, in spite of which the patient developed HAM. Once the diagnosis of HAM was established, antiretroviral therapy was restarted, and intravenous pulses of methylprednisolone were periodically administered with transient initial improvement. Later on, the patient experienced neurological deterioration becoming wheelchair dependent. Since the occurrence of this case, HTLV-1 screening has become mandatory for solid organ transplantation in the Spanish province of Navarra, and the same should happen worldwide.
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Trasplante de Riñón/efectos adversos , Paraparesia Espástica Tropical/etiología , Trasplantes/virología , Antivirales , Femenino , Humanos , Persona de Mediana Edad , Paraparesia Espástica Tropical/tratamiento farmacológico , Raltegravir Potásico/uso terapéutico , Zidovudina/uso terapéuticoRESUMEN
BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces functional changes, ultimately causing chronic spinal cord inflammation. We evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets infected cells, in patients with HAM-TSP. METHODS: In this uncontrolled, phase 1-2a study, we assessed the safety, pharmacokinetics, and efficacy of mogamulizumab in patients with glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21 patients received a single infusion of mogamulizumab (at doses of 0.003 mg per kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those patients, 19 continued on to the phase 2a study and received infusions, over a period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg per kilogram at 12-week intervals. RESULTS: The side effects of mogamulizumab did not limit administration up to the maximum dose (0.3 mg per kilogram). The most frequent side effects were grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each in 33%). The dose-dependent reduction in the proviral load in peripheral-blood mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI], 51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day 29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI, 10.7 to 31.4] in the neopterin level) was maintained with additional infusions throughout the phase 2a study. A reduction in spasticity was noted in 79% of the patients and a decrease in motor disability in 32%. CONCLUSIONS: Mogamulizumab decreased the number of HTLV-1-infected cells and the levels of inflammatory markers. Rash was the chief side effect. The effect of mogamulizumab on clinical HAM-TSP needs to be clarified in future studies. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .).