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In the original publication of the article, Table 5 was published with incorrect contents. The correct Table 5 is given in this correction.
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Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm associated with the human T-cell leukemia virus type-I (HTLV-1); prognosis still remains very poor. We retrospectively reviewed the treatment of 198 patients with acute-, lymphoma- and unfavorable chronic-type ATL (aggressive ATL) diagnosed from 2005 to 2014 in a hospital located in an area of Japan in which HTLV-1 is highly endemic. One-hundred forty-three, and 35 patients were treated using OPEC/MPEC and VCAP-AMP-VECP, respectively. OPEC/MPEC was mainly used until around 2010, and gradually switched to VCAP-AMP-VECP, especially for younger patients. The 2-year overall survival for patients treated by VCAP-AMP-VECP was significantly higher than that using OPEC/MPEC for patients < 70 years old (y.o.), but not for patients ≥ 70 y.o. A less intensive chemotherapy OPEC/MPEC could be performed without reducing dose intensity, even in elderly patients, and its therapeutic outcome is not inferior to that of VCAP-AMP-VECP. It is difficult to draw definite conclusion from this small retrospective study; however, OPEC/MPEC may represent an alternative option for elderly patients with aggressive ATL.
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Infecções por Deltaretrovirus/epidemiologia , Leucemia-Linfoma de Células T do Adulto/terapia , Progressão da Doença , Hospitais/estatística & dados numéricos , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T do Adulto/epidemiologia , Estudos RetrospectivosRESUMO
Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm with very poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been reported as a curative treatment modality for ATL. However, there are no reports comparing chemotherapy alone with allo-HSCT in ATL. In this report, we retrospectively analyzed data for patients treated with (n = 29, median age 55 years) or without allo-HSCT (n = 37, median age 58 years) for ATL in Kagoshima University Hospital, located in one of the most endemic areas of human T cell lymphotropic leukemia virus type 1 infection. Forty patients (61%) started coordination for allo-HSCT. Ten patients (34.4%) received allo-HSCT while in complete remission (CR), whereas the others were not in CR. Twenty-five patients (86.2%) received reduced-intensity conditioning, and the others received myeloablative conditioning. With a median follow-up period for survivors of 41 months (range, 5 to 125 months), the 3-year overall survival (OS) rate from first chemotherapy for all patients (with or without allo-HSCT) was 35.2%. The 3-year OS from first chemotherapy for patients who received allo-HSCT or only chemotherapy was 44.9% and 27.7%, respectively. Univariate analyses revealed that high serum soluble IL-2 receptor (sIL-2R) levels (≥ 2000 U/mL) just before the conditioning regimen and progressive disease (PD) status at HSCT (according to Japan Clinical Oncology Group Study 0907 criteria) were significant risk factors for OS in the allo-HSCT group. Multivariate analyses revealed that PD status was a significant risk factor for OS in the allo-HSCT group. In the chemotherapy-only group, the 3-year OS rate was 61.5% (95% CI, 30.8% to 81.8%) in patients with serum sIL-2R levels < 2000 U/mL for > 3 months. In contrast, the 3-year OS rate was 5.7% (95% CI, .4% to 22.4%) in patients who did not achieve serum sIL-2R levels < 2000 U/mL for >3 months. Our single-center cohort experience indicates that chemosensitivity is the most important prognostic factor for OS in ATL patients and the use of allo-HSCT is limited in chemorefractory patients with aggressive ATL disease. In the chemosensitive patients, allo-HSCT demonstrated a tendency toward better OS. Further clinical studies are warranted to determine optimal treatments for patients who are less sensitive to conventional chemotherapy.
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Antineoplásicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto/mortalidade , Leucemia-Linfoma de Células T do Adulto/terapia , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Taxa de SobrevidaRESUMO
Interleukin-7 (IL-7) mediates T-cell homeostasis through its effects on T-cell development, survival and function. In human T-cell lymphotropic virus type 1 (HTLV-1) infection, which is causally implicated in adult T-cell leukemia (ATL), the efficiency with which CD8(+) cytotoxic T-lymphocytes (CTLs) clear HTLV-1-infected cells mediates viral control and may be related to disease progression. We report here that CD127 expression in CD8(+) T-cells is independently related to disease status, and that exogenous IL-7 enhances CD8(+) T-cell survival and clearance of HTLV-1 infected cells in vitro. We conclude that CD127 down-regulation may be associated with disease status in HTLV-1 infection, and propose that exogenous IL-7 may be useful immunotherapy or cytokine adjuvant for an anti-ATL therapeutic vaccine.
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Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Interleucina-7/farmacologia , Leucemia-Linfoma de Células T do Adulto/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologiaRESUMO
OBJECTIVE: The ability of the ImmuKnow (Cylex) assay to predict the risk of infection in rheumatoid arthritis (RA) patients receiving synthetic or biological disease-modifying antirheumatic drugs (DMARDs) was examined. METHODS: The amount of adenosine triphosphate (ATP) produced by CD4+ cells in response to phytohemagglutinin was measured in whole blood from 117 RA patients without infection versus 17 RA patients with infection, and compared with results in 75 healthy controls. RESULTS: The mean ATP level was significantly lower in patients with infection compared to both healthy controls (P < 0.0005) and patients without infection (P = 0.040). Also, the mean ATP level in patients without infection was significantly lower than that in healthy controls (P = 0.012). There was no correlation between the ATP level and the Disease Activity Score in 28 joints. CONCLUSION: ImmuKnow assay results may be effective in identifying RA patients at increased risk of infection, but the results showed no correlation with RA activity. Larger studies are required to establish the clinical advantages of this assay in RA treatment.
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Trifosfato de Adenosina/sangue , Artrite Reumatoide/complicações , Linfócitos T CD4-Positivos/metabolismo , Infecções/complicações , Adulto , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Feminino , Humanos , Imunoensaio/métodos , Imunossupressores/efeitos adversos , Infecções/etiologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Valor Preditivo dos Testes , Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid. MATERIALS AND METHODS: Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated. RESULTS: The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug-resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone. CONCLUSION: The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II.
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Apoptose , Dioxolanos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Hyptis/metabolismo , Extratos Vegetais/farmacologia , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/farmacologia , Citotoxinas/química , Dano ao DNA , Etoposídeo/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Leucemia de Células T/tratamento farmacológico , Lignanas/química , Mitoxantrona/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismoRESUMO
Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A*0201 tetramer and an HTLV-1 Tax/HLA-A*2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A*2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A*0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1.
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Antígenos de Diferenciação/metabolismo , Doenças Autoimunes/imunologia , Antígeno B7-H1/metabolismo , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Linfócitos T Citotóxicos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Bloqueadores/farmacologia , Antígenos de Diferenciação/genética , Doenças Assintomáticas , Doenças Autoimunes/complicações , Doenças Autoimunes/fisiopatologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Portador Sadio , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/imunologia , Antígeno HLA-A2/metabolismo , Antígeno HLA-A24/metabolismo , Infecções por HTLV-I/complicações , Infecções por HTLV-I/fisiopatologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Imunofenotipagem , Linfoma de Células T , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical , Receptor de Morte Celular Programada 1 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/virologiaRESUMO
Human T-cell lymphotropic virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The different patterns of clinical diseases are thought to be linked to immunogenetic host factors. A variety of autoimmune diseases, such as Sjögren's syndrome, have been reported in persons infected with HTLV-1, although the precise relationship between these disorders and HTLV-1 infection remains unknown. There is no report on the repertoire of HTLV-1-specific CD8+ T-cells in HAM/TSP patients or carriers with autoimmune diseases, both characterized by an abnormal immune state. In this study, to characterize HTLV-1-specific CD8+ T-cells in asymptomatic HTLV-1 carriers, HAM/TSP patients and carriers with autoimmune diseases, we examined the frequency and diversity of HTLV-1-specific CD8+ T-cells using HTLV-1 tetramers. HTLV-1 Env-specific CD8+ T-cells were significantly more frequent in HAM/TSP and carriers with autoimmune diseases compared with asymptomatic HTLV-1 carriers, while the frequency of HTLV-1 Tax-specific CD8+ T-cells was not significantly different among them. CD8+ cells binding to HTLV-1 Tax tetramers in carriers with autoimmune diseases were significantly reduced compared with HAM/TSP patients. This study demonstrates the importance of CD8+ T-cells recognizing HTLV-1 Env-tetramers in HAM/TSP patients and carriers with autoimmune diseases, thereby suggesting that the diversity, frequency and repertoire of HTLV-1 Env-specific CD8+ T-cell clones may be related to the hyperimmune response in HAM/TSP and carriers with autoimmune diseases, although different immunological mechanisms may mediate the hyperimmunity in these conditions.
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Doenças Autoimunes/imunologia , Epitopos , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Paraparesia Espástica Tropical/imunologia , Linfócitos T Citotóxicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Epitopos/imunologia , Epitopos/metabolismo , Produtos do Gene tax/imunologia , Produtos do Gene tax/metabolismo , Variação Genética , Antígenos HLA-A/química , Antígenos HLA-A/imunologia , Antígenos HLA-A/metabolismo , Teste de Histocompatibilidade , Humanos , Pessoa de Meia-Idade , Ligação Proteica , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Adulto JovemRESUMO
OBJECTIVE: Fibromyalgia syndrome (FMS) is a chronic syndrome characterized by widespread pain with tenderness in specific areas. We examined the applicability of Waon therapy (soothing warmth therapy) as a new method of pain treatment in patients with FMS. METHODS: Thirteen female FMS patients (mean age, 45.2+/-15.5 years old; range, 25-75) who fulfilled the criteria of the American College of Rheumatology participated in this study. Patients received Waon therapy once per day for 2 or 5 days/week. The patients were placed in the supine or sitting position in a far infrared-ray dry sauna maintained at an even temperature of 60 degrees C for 15 minutes, and then transferred to a room maintained at 26-27 degrees C where they were covered with a blanket from the neck down to keep them warm for 30 minutes. Reductions in subjective pain and symptoms were determined using the pain visual analog scale (VAS) and fibromyalgia impact questionnaire (FIQ). RESULTS: All patients experienced a significant reduction in pain by about half after the first session of Waon therapy (11-70%), and the effect of Waon therapy became stable (20-78%) after 10 treatments. Pain VAS and FIQ symptom scores were significantly (p<0.01) decreased after Waon therapy and remained low throughout the observation period. CONCLUSION: Waon therapy is effective for the treatment of fibromyalgia syndrome.
Assuntos
Fibromialgia/terapia , Hipertermia Induzida , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Medição da Dor , Resultado do TratamentoRESUMO
A 23-year-old man with Philadelphia-chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his HLA-identical brother in first hematological remission following induction chemotherapy which included imatinib. He had no acute graft-versus-host disease (GVHD), and 4.5 months after HSCT, he had a molecular relapse (180,000 copies/mug RNA of minor bcr/abl transcripts (m-bcr/abl) without mutation in 22 sites including the p-loop region). Following discontinuation of cyclosporine A, imatinib (600 mg daily) was restarted and 4 days later donor lymphocyte infusion (DLI) (5 x 10(7)/kg of CD3(+) cells) was given. In 2 weeks, the marrow m-bcr/abl became undetectable. He received two further DLIs and imatinib was continued at a reduced dose of 400 mg a day. At the time of this report, he remains in complete hematological remission more than 33 months after allo-HSCT and persists in the second molecular remission for longer than 24 months. During this clinical course, he became positive for anti-nuclear antibody after second DLI, without any other manifestations of GVHD. The standard treatment for Ph(+) ALL relapsing after allo-HSCT still remains to be established. Imatinib in combination with DLI for early molecular relapse may be a promising option.
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Transplante de Células-Tronco Hematopoéticas , Doadores Vivos , Transfusão de Linfócitos , Cromossomo Filadélfia , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Benzamidas , Ciclosporina/administração & dosagem , Humanos , Mesilato de Imatinib , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Indução de Remissão , Irmãos , Transplante HomólogoRESUMO
CD22 is an important immunotherapeutic target on B-cell malignancies, particularly hairy cell leukemia (HCL), but its soluble extracellular domain, sCD22, has not yet been reported in the blood. By immunoaffinity and enzyme-linked immunosorbent assay techniques using anti-CD22 monoclonal antibodies, we identified the 100-kDa extracellular domain of CD22 and an 80-kDa processed form in serum of patients with HCL. The median sCD22 level measured by enzyme-linked immunosorbent assay was 18 ng/mL for 93 patients with HCL. sCD22 levels varied from 2.1 to 163 ng/mL and were higher (P < .001) than 23 normal donors (median, 0.6 ng/mL). More than 95% of normal donors had sCD22 levels less than 1.9 ng/mL. sCD22 levels were proportional to concentrations of circulating HCL cells (P = .002), and HCL spleen size (P < .001). sCD22 levels normalized with complete but not partial response to treatment. sCD22 levels up to 300 ng/mL had less than a 2-fold effect on the cytotoxicity of the anti-CD22 recombinant immunotoxin BL22. sCD22 levels may be useful to follow in patients with HCL and may be more specific than sCD25 in patients with CD22(+)/CD25(-) disease. Trials are listed on www.cancer.gov as NCT00002765, NCT00021983, NCT00074048, NCT00085085, NCT00337311, and NCT00462189.
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Leucemia de Células Pilosas/diagnóstico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Técnicas e Procedimentos Diagnósticos , Ensaio de Imunoadsorção Enzimática , Humanos , Imunotoxinas/toxicidade , Leucemia de Células Pilosas/tratamento farmacológico , Peso Molecular , Solubilidade , Carga TumoralRESUMO
To increase the availability of alternative stem-cell donors for patients with adult T-cell leukemia (ATL), we examined the feasibility of HLA-incompatible family transplantation, especially from a grown-up child (donor) to a parent (recipient). Since January 2004, seven patients with advanced-phase ATL (three males and four females, median age 59 years), for whom a timely HLA-compatible donor was unavailable, were enrolled. All patients received allografts from their HLA-incompatible sons with reduced-intensity conditioning stem cell transplantation (RIST). Combined graft-versus-host disease (GVHD) prophylaxis involved cyclosporine A or tacrolimus, mycophenolate mofetil or corticosteroid, and short-term methotrexate. All patients achieved prompt engraftment, and there was no 100-day relapse-related mortality. Only one patient had grade-IV acute-GVHD, but this was resolved. The median follow-up period was 251 days (range 112-1,018 days), and the estimated 1-year overall and 1-year progression-free survival rates were 57.1 and 28.6%, respectively. Four patients died, with causes of death being relapse (n = 2), transplantation-associated microangiopathy (n = 1), and septicemia (n = 1). Three are currently alive: two are in complete remission and one has stable disease. Despite a high rate of relapse, RIST using an allograft from an HLA-incompatible grown-up child donor may be feasible for patients with advanced-phase ATL, and may prolong survival.
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Transplante de Células-Tronco Hematopoéticas , Leucemia de Células T/terapia , Transfusão de Linfócitos , Condicionamento Pré-Transplante , Doação Dirigida de Tecido , Feminino , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Transplante HomólogoRESUMO
We examined human T-lymphotropic virus type I (HTLV-I) infection among patients with myelodysplastic syndrome (MDS), refractory anemia with excess of blasts (RAEB)/RAEB in transformation (RAEBt) and acute myelogenous leukemia (AML). The study population consisted of 151 patients: 46 with MDS RAEB/RAEBt and 105 with AML (M1, n = 15; M2, n = 39; M3, n = 18; M4, n = 19; M5, n = 9; M6, n = 3; M7, n = 2). As a reference, we examined 92 patients with refractory anemia (RA) and 405 patients with cardiovascular diseases (CVD). Thirteen patients with RAEB/RAEBt (28.3%), 11 with AML (11.6%), 27 with RA (29.3%), and 45 with CVD (11.0%) were positive for HTLV-I. Seven AML patients with HTLV-I infection had M3 acute promyelocytic leukemia (APL). The prevalences of HTLV-I infection among patients with RAEB/RAEBt (P < 0.001), APL (P = 0.001), and RA (P < 0.001) were significantly higher than that in patients with CVD. The prevalences of HTLV-I infection were still significantly higher in patients with RAEB/RAEBt (P = 0.007), APL (P = 0.017) and RA (P < 0.001) than in those with CVD matched by sex and age. Platelet counts and survival times of RAEB/RAEBt patients with infection were significantly lower than those of patients without infection.
Assuntos
Anemia Refratária com Excesso de Blastos/virologia , Infecções por HTLV-I/epidemiologia , Leucemia Promielocítica Aguda/virologia , Síndromes Mielodisplásicas/virologia , Adulto , Idoso , Transformação Celular Neoplásica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prevalência , Taxa de SobrevidaRESUMO
Adult T cell leukemia (ATL) is one of the most refractory malignant hematological diseases. Our previous studies demonstrated HTLV-1Tax protein involvement in clinical manifestation of the aggressive type of ATL and suggested the potential application of agents to inhibit Tax expression for ATL treatment. In the present study, we first examined Tax involvement in the resistance to VP-16-induced apoptosis using four HTLV-1 infected T cell clones and cTax DNA-transfected cells. Next, we examined whether cyclosporin A reduced expression of Tax and its related transfer factors on Western blot and CAT assay. We further investigated whether cyclosporin A in combination with VP-16 can induce apoptosis in HTLV-1 infected T cells. Tax-producing T cells, K3T and F6T, were resistant to VP-16 induced growth inhibition compared with that of the nonproducing cells, S1T and Su9T01. Experiments using S1T and Tax-expressing cDNA-transfected S1T demonstrated Tax-induced resistance to VP-16 induction of apoptosis by DNA ladder formation. Cyclosporin A reduced Tax expression in K3T by Western blot analysis and on CAT assay, showing maximal reduction of 61% and 60% compared to control culture using LTR CAT transfected Jurkat cells and K3T cells, respectively. Cyclosporin A also reduced the nuclear expression of two Tax-related transfer factors, ATF-1 and ATF-2 on Western blot. Cyclosporin A alone did not show any cytotoxicity by itself, but sensitized cells to VP-16 when combined with VP-16. Cyclosporin A may be a useful anti-ATL agent when combined with other anti-cancer agents possibly related to Tax inhibition.
Assuntos
Antineoplásicos/farmacologia , Ciclosporina/farmacologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Produtos do Gene tax/genética , Proteína Vmw65 do Vírus do Herpes Simples/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Etoposídeo/farmacologia , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , HumanosRESUMO
OBJECTIVE: Human T lymphotropic virus type I (HTLV-I) may be associated with some connective tissue autoimmune diseases, including systemic lupus erythematosus (SLE). To determine the relationship between HTLV-I infection and SLE, we examined the clinical manifestations of SLE patients with HTLV-I infection. METHODS: Eighty-nine patients with SLE were screened for antibodies to HTLV-I by electrochemiluminescence immunoassay. The presence of HTLV-I proviral sequences in peripheral blood mononuclear cells (PBMC) was determined by real-time polymerase chain reaction (PCR) quantification and Southern blotting analysis. The differences in clinical manifestations between HTLV-I-seropositive and seronegative patients with SLE were analyzed statistically. RESULTS: Fourteen of 89 (15.7%) patients were HTLV-I seropositive. All PBMC samples from 11 patients tested by PCR and 3 samples from 10 patients tested by Southern blotting analysis were positive for HTLV-I-related sequences. The age of HTLV-I-seropositive patients with SLE was significantly higher than that of seronegative patients (median 60 vs 42 yrs; p < 0.0005). The age at onset of SLE in HTLV-I-seropositive patients was also significantly higher than that of seronegative patients (median 45.5 vs 30 yrs; p <0.0005). The lymphocyte count in HTLV-I-seropositive SLE patients was significantly higher than that of seronegative patients (median 1740 vs 1066/microl; p = 0.027). The maintenance dose of prednisolone in HTLV-I-seropositive patients with SLE was significantly lower than that in seronegative patients (median 5 vs 9 mg/day; p = 0.012). CONCLUSION: This is the first report of the differences in clinical manifestations between SLE patients with and without HTLV-I infection. Our results suggest some involvement of HTLV-I in the pathogenesis of SLE.
Assuntos
Infecções por HTLV-I/fisiopatologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Lúpus Eritematoso Sistêmico/fisiopatologia , Lúpus Eritematoso Sistêmico/virologia , Adulto , Idoso , Antirreumáticos/administração & dosagem , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Infecções por HTLV-I/complicações , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Japão/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prednisolona/administração & dosagem , Estudos Soroepidemiológicos , Testes SorológicosRESUMO
Previous studies have suggested that higher anti-human T-lymphotropic virus 1 (HTLV-1) antibody titer and lower anti-HTLV-1 Tax antibody reactivity are risk factors for adult T-cell leukemia/lymphoma. In the present study, we analyzed the relationships between these factors and clarified their significance. Forty-five carriers were examined for anti-HTLV-1 and anti-Tax antibody by ELISA. In addition, 43 of the 45 carriers with HLA-A*0201 and/or A*2402 were examined for frequency of Tax-specific cytotoxic T lymphocytes (CTLs) using HTLV-1/HLA tetramers, and 44 were examined for proviral load by real-time PCR. The relationships between these factors were analyzed statistically. The frequencies of Tax11-19 and Tax301-309-specific CTLs were significantly higher in the anti-Tax antibody-positive group as compared with the antibody-negative group (P = 0.002 and 0.033, respectively). Anti-HTLV-1 antibody titer had a positive correlation with proviral load (P = 0.019), whereas anti-Tax antibody did not show a significant correlation. Higher frequencies of both Tax11-19 and Tax301-309-specific CTLs are related to a reduction in proviral load (P = 0.017 and 0.015, respectively). Synergistic interactions of humoral and cellular immunity against Tax protein were demonstrated in HTLV-1 carriers. Tax-specific CTL may reduce HTLV-1 proviral load to prevent asymptomatic carriers from developing adult T-cell leukemia/lymphoma.
Assuntos
Portador Sadio/imunologia , Portador Sadio/virologia , Produtos do Gene tax/imunologia , Anticorpos Anti-HTLV-I/sangue , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Feminino , Produtos do Gene tax/genética , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Provírus/imunologia , Provírus/isolamento & purificação , Linfócitos T Citotóxicos/imunologiaRESUMO
Behçet's disease (BD) is a systemic inflammatory disorder of unknown etiology, and rarely complicated with myelodysplastic syndrome (MDS). In the present study, we investigated the morphological myelodysplasia and apoptotic rate of bone marrow cells in 15 patients with BD in comparison with MDS patients. Morphological myelodysplasia of bone marrow cells was detected in 53.3% of BD, but none showed chromosomal abnormalities. The apoptotic rate in BD patients (26.1 +/- 8.4%) was significantly higher in normal controls (11.3 +/- 2.4%; p < 0.005) and significantly lower in patients with MDS (50.8 +/- 14.0%; p < 0.0001). These findings suggest that myelodysplasia in patients with BD is more frequent than expected, and possibly due to excess induction of apoptosis of bone marrow cells in BD. However, the rate of apoptotic bone marrow cells is lower than MDS, which may explain the slight peripheral cytopenia in BD, distinct from that in MDS.
Assuntos
Síndrome de Behçet/complicações , Síndrome de Behçet/patologia , Células da Medula Óssea/patologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Apoptose/fisiologia , Síndrome de Behçet/genética , Feminino , Antígenos HLA-B/genética , Antígeno HLA-B51 , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genéticaRESUMO
Human T cell lymphotropic virus type 1 (HTLV-1)-specific CTL are thought to be immune effectors that reduce the risk of adult T cell leukemia (ATL). However, in vivo conditions of anti-HTLV-1 CTL before and after ATL development have yet to be determined. To characterize anti-HTLV-1 CTL in asymptomatic HTLV-1 carriers (AC) and ATL patients, we analyzed the frequency and diversity of HTLV-1-specific CD8+ T cells in PBMC of 35 AC and 32 ATL patients using 16 distinct epitopes of HTLV-1 Tax or Env/HLA tetramers along with intracellular cytolytic effector molecules (IFN-gamma, perforin, and granzyme B). Overall frequency of subjects possessing Tax-specific CD8+ T cells was significantly lower in ATL than AC (53 vs 90%; p = 0.001), whereas the difference in Env-specific CD8+ T cells was not statistically significant. AC possessed Tax11-19/HLA-A*0201-specific tetramer+ cells by 90% and Tax301-309/HLA-A*2402-specific tetramer+ cells by 92%. Some AC recognized more than one epitope. In contrast, ATL recognized only Tax11-19 with HLA-A*0201 and Tax301-309 with HLA-A*2402 at frequencies of 30 and 55%. There were also significant differences in percentage of cells binding Tax11-19/HLA-A*0201 and Tax301-309/HLA-A*2402 tetramers between AC and ATL. Anti-HTLV-1 Tax CD8+ T cells in AC and ATL produced IFN-gamma in response to Tax. In contrast, perforin and granzyme B expression in anti-HTLV-1 CD8+ T cells of ATL was significant lower than that of AC. Frequency of Tax-specific CD8+ T cells in AC was related to proviral load in HLA-A*0201. These results suggest that decreased frequency, diversity, and function of anti-HTLV-1 Tax CD8+ T cell clones may be one of the risks of ATL development.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Leucemia-Linfoma de Células T do Adulto/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/virologia , Células Clonais , Feminino , Produtos do Gene tax/imunologia , Antígenos HLA/imunologia , Humanos , Interferon gama/biossíntese , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologiaRESUMO
OBJECTIVE: To investigate the effects of the recombinant immunotoxin dsFv anti-FRbeta-PE38, which consists of the disulfide-stabilized Fv fragment (dsFv) of the anti-folate receptor beta (anti-FRbeta) antibody and the 38-kd portion of Pseudomonas exotoxin A (PE38), on the activation and proliferation of cells that function in inflammatory and degradative processes in rheumatoid arthritis (RA) synovial tissue. METHODS: The Ig VH-PE38 fusion protein and the Ig VL protein were produced in Escherichia coli, and then joined with a disulfide bond by engineering cysteine residues in the framework regions of these proteins. The effects of dsFv anti-FRbeta-PE38 on the activation and proliferation of cells in RA synovial tissue were investigated by immunohistochemistry; the numbers of cells expressing CD68, vascular cell adhesion molecule 1, angiopoietin 1, CD34, proliferating cell nuclear antigen, and interleukin-6 and the numbers of apoptotic cells were counted in RA synovial tissue engrafted into SCID mice treated or not treated with dsFv anti-FRbeta-PE38. The effects of dsFv anti-FRbeta-PE38 on the generation of osteoclasts from RA adherent synovial mononuclear cells in vitro was investigated by counting the number of resorption pits on dentin slices treated or not treated with dsFv anti-FRbeta-PE38. RESULTS: Administration of dsFv anti-FRbeta-PE38 reduced the numbers of macrophages, activated fibroblast-like cells, endothelial cells, and proliferating cells and increased the numbers of apoptotic cells in RA synovial tissue engrafted into SCID mice. In vitro, the generation of osteoclasts from RA adherent synovial mononuclear cells was largely suppressed by treatment with dsFv anti-FRbeta-PE38. CONCLUSION: Our findings show that dsFv anti-FRbeta-PE38 immunotoxin would be a promising tool for the treatment of RA synovitis, especially when administered intraarticularly.