Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.396
Filtrar
1.
Medicine (Baltimore) ; 99(1): e18624, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895820

RESUMO

The purpose of this study was to evaluate neutropenia following intravenous immunoglobulin (IVIG) therapy in adults with immune thrombocytopenic purpura (ITP).Our analysis included 88 patients with ITP, who received IVIG from January 2006 to March 2016, at Pusan National University Hospital in Korea. Their white blood cell (WBC) count and absolute neutrophil count (ANC) before and after IVIG treatment were analyzed.Of 88 patients, 24 patients (27.3%) were male, and 64 patients (72.7%) were female. Neutropenia developed in 8 patients (18.7%) after IVIG treatment. In patients with a decrease in WBC count and ANC compared to baseline, median WBC count decreased from 6280/µL to 4530/µL after IVIG therapy, and median ANC decreased from 3840/µL to 2840/µL after IVIG therapy. The neutropenia induced by IVIG had resolved spontaneously after several days, and the mean recovery time was 8.72 days after the completion of the IVIG treatment. During the neutropenic episodes, only one patient developed neutropenic fever, which subsided soon without any treatment.The results of this study suggest that IVIG may cause neutropenia commonly in adults with ITP, and it seems to be transient and self-limited. This study is meaningful as the first report that not only pediatric ITP patients may develop neutropenia post IVIG administration, but also adult patients suffering ITP.


Assuntos
Imunoglobulinas Intravenosas/efeitos adversos , Neutropenia/etiologia , Púrpura Trombocitopênica Idiopática/terapia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/imunologia , Estudos Retrospectivos , Adulto Jovem
2.
Medicine (Baltimore) ; 98(43): e17608, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651870

RESUMO

This study aims to investigate the changes of cytokines and the effect of programmed death ligand 1 (PD-L1) signaling pathway on T cell function in patients with immune thrombocytopenic purpura (ITP).Totally, 40 untreated ITP patients were recruited and 30 healthy people were recruited as the healthy control. Then whole blood of ITP patients and healthy control was collected, respectively. The sPD-L1/anti-PD-1 was used to activate or block the programmed death (PD-1)/PD-L1 signaling pathway. The expression of PD-1 and PD-L1 on peripheral blood mononuclear cells (PBMCs) were detected by flow cytometry. PBMCs were treated with cluster of differentiation (CD3), cluster of differentiation 28 (CD28), and phytohaemagglutinin (PHA) for 48 hours. Serum levels of sPD-1, sPD-L1, and cytokines were measured by enzyme-linked immunosorbent assay (ELISA).Compared with the healthy control group, the percentages of PD-1+CD3+CD4+ T cells and PD-L1+HLA-DR+CD11c+ DC cells were increased in ITP patients. The levels of interferon-gamma (IFN-γ), interleukin-17 (IL-17), and sPD-1 in the serum of ITP patients were increased, while IL-4 and transforming growth factor-ß (TGF-ß) were decreased. Additionally, the level of sPD-1 was negatively correlated with the platelet count. Consistently, after treatment with CD3, CD28, and PHA, IFN-γ and IL-17 levels in culture supernatant of PBMCs from ITP patients were significantly higher than those from healthy controls whereas IL-4 and TGF-ß levels were significantly lower. Furthermore, IFN-γ and IL-17 levels secreted by PBMCs from ITP patients decreased after sPD-L1 administration, however, IL-4 and TGF-ß levels were increased. The level of IFN-γ in ITP group remained higher after anti-PD-1 blockage, but the levels of IL-4, TGF-ß, and IL-17 were not significantly influenced.sPD-1 may cause the dysfunction of PD-1/PD-L1 signaling pathway, and its level is related to the severity of ITP patients. Activation of PD-1/PD-L1 with sPD-L1 may restore the imbalance of Th1/Th2 and Treg/Th17 cell subtypes in ITP patients but anti-PD-1 may exacerbate disease by enhancing IFN-γ production.


Assuntos
Antígeno B7-H1/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Linfócitos T Reguladores/imunologia , Equilíbrio Th1-Th2/fisiologia , Células Th17/imunologia , Adulto , Antígenos CD28/imunologia , Complexo CD3/imunologia , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/imunologia , Receptor de Morte Celular Programada 1/fisiologia , Púrpura Trombocitopênica Idiopática/sangue , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
3.
Biomed Res Int ; 2019: 1050285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380412

RESUMO

Background: Th17/Treg balance skews towards Th17 in ITP patient. IRF4 has been highlighted for its close relationship to the immunosuppressive function of Treg cells and the IL-17 synthesis in CD4+ T cells. This study was aimed at examining the effects of IRF4 to the Th17/Treg cells in patients with ITP. Methods: Treg and Teff cells were isolated from PBMCs of newly diagnosed ITP patients. The percentages of CD4+CD25hiFoxp3+Treg cells and the CD3+CD4+IL-17+Th17 cells were detected by flow cytometry. After being cultured, the supernatants of Tregs were collected for IL-10 concentration test. The IRF4 levels of Tregs were measured. Teffs were cultured alone or with Tregs for 24 hours. Then the supernatants were collected for IL-17 concentration test. The binding intensity of IRF4 to the gene IL-10 in Treg cells was detected by ChIP-qPCR. Metabolic assays for Teffs and Tregs were performed with Agilent Seahorse XF96 Analyzer. Results: The secretion of IL-10 by Tregs was decreased in ITP patients. The intensity of IRF4 binding to IL-10 DNA of Tregs in patients was higher than that of normal controls and Teffs in ITP patients. The expressions of IRF4 of Tregs in ITP patients were remarkably lower than that of healthy controls. The percentage of Th17 cells in healthy controls was significantly increased after IRF4 mRNA silencing. Abnormal metabolism of Treg and Teff cells was found in ITP patients. Conclusion: The skewed ratio of Th17/Treg cells and dysfunction of Treg cells in newly diagnosed ITP patients was at least partly caused by IRF4 dysfunction. The underlying mechanism might be the impact of IRF4 on the metabolism of Treg and Teff cells.


Assuntos
Fatores Reguladores de Interferon/genética , Interleucina-10/genética , Púrpura Trombocitopênica Idiopática/genética , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunossupressão/métodos , Fatores Reguladores de Interferon/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
4.
Clin Chim Acta ; 498: 68-75, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31421121

RESUMO

BACKGROUND: Platelet antibodies can lead to clinical diseases such as platelet transfusion refractoriness (PTR), fetal/neonatal alloimmune thrombocytopenia (FNAIT), etc. This study is aimed at understanding CD36 expression, platelet alloantibody distribution in different populations in Northern China, and effects of platelet alloantibodies on pregnancy. STUDY DESIGN AND METHODS: Whole blood samples of 612 subjects including hematological patients, pregnant women, and blood donors were collected at a single center, then CD36 expressions were determined, followed by platelet antibody screening and characterization of platelet antibody specificity. A retrospective analysis was performed in 1552 pregnant women admitted to Department of Obstetrics, in order to investigate FNAIT occurrence. RESULTS: Rate of CD36 deficiency expression was 2.12% (13/612), all cases exhibited type II deficiency without type I deficiency being detected, and such rate is lower than that in Southern China (3.43%), Japanese (4.87%) and in the black people (4.18%), and higher than that in the White people (0.09%). Positive rates of platelet antibody screening in hematological patient group (6.86%, 14/204) and in pregnant women group (6.31%, 13/206) are higher than that in blood donor group (0.49%, 1/202), P < .01. Out of 1552 pregnant women, there were not children with FNAIT. CONCLUSION: The frequency of CD36 deficiency in northern China was low, all of them were type II deficiency, and no CD36 antibody was detected. It is speculated that the risk of immune-related thrombocytopenia caused by CD36 deficiency in this population is very low. Platelet antibodies should be monitored early in patients with hematological and multiple miscarriages pregnant.


Assuntos
Plaquetas/imunologia , Antígenos CD36/deficiência , Isoanticorpos/farmacologia , Doadores de Sangue , China/epidemiologia , Feminino , Doenças Hematológicas/imunologia , Humanos , Isoanticorpos/metabolismo , Masculino , Gravidez , Complicações na Gravidez/imunologia , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/imunologia , Estudos Retrospectivos , Trombocitopenia Neonatal Aloimune/etiologia , Trombocitopenia Neonatal Aloimune/imunologia
5.
Intern Med ; 58(21): 3083-3086, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292378

RESUMO

Objective Chest physicians often encounter patients with interstitial pneumonia with autoimmune features. However, there have so far been few reports of patients presenting with concurrent immune thrombocytopenia (ITP) and interstitial pneumonia. The prevalence of interstitial pneumonia in patients with ITP is less well known. Methods We surveyed patients diagnosed with ITP and interstitial pneumonia at the departments of Hematology and Respiratory Medicine to evaluate the association between these diseases. Results Among 73 patients with ITP, 7 patients (9.6%) presented with interstitial pneumonia, including 4 patients (2%) who developed ITP in the course of 204 patients with interstitial pneumonia. All 7 patients were men. Four patients were positive for some autoantibodies. Two patients had autoimmune diseases other than ITP. There were significant differences in age and gender between the ITP patients with and without interstitial pneumonia. Conclusion The present study suggests the possibility that the development of ITP, other autoimmune diseases, and interstitial pneumonia may be mutually associated. Advanced age and male sex in ITP may be significant predisposing factors for interstitial pneumonia. Clinicians should be aware of the potential for the coexistence of these diseases.


Assuntos
Autoanticorpos/sangue , Doenças Pulmonares Intersticiais/complicações , Púrpura Trombocitopênica Idiopática/complicações , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/complicações , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/diagnóstico por imagem , Púrpura Trombocitopênica Idiopática/imunologia , Fatores de Risco , Fatores Sexuais , Tomografia Computadorizada por Raios X
6.
Chin J Integr Med ; 25(7): 483-489, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31278626

RESUMO

Chronic primary immune thrombocytopenia (CITP) is the most common acquired autoimmune disease that seriously threaten the physical and mental health of patients. Compared with Western medicine treatment, the intervention and treatment of Chinese medicine (CM) has shown certain therapeutic advantages. This paper reviewed the new pathogenesis progress on T cell immune abnormality in CITP, and CM studies on interferes effects of cellular immune regulation of CITP in recent years. Qi deficiency failing to control blood and internal obstruction of blood stasis are the two common types of CM syndromes in CITP patients, the corresponding treatments include invigorating Pi (Spleen), supplementing qi, activating blood, as well as tonifying qi and activating yang, regulating Gan (Liver) to invigorate Pi. The authors also mentioned the problems in the research field of CM for CTIP treatment, and put forward new ideas for the research in the future.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Imunidade Celular , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/imunologia , Pesquisa , Hemorragia/tratamento farmacológico , Humanos
7.
Drugs ; 79(12): 1305-1319, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292909

RESUMO

Eltrombopag is an orally available thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP). Beyond the effect on megakaryopoiesis, the drug also showed a stimulating effect on the hematopoietic stem cell with consistent clinical efficacy in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Eltrombopag is highly effective in ITP and less so in AA and MDS. This observation underlines the importance of residual normal hematopoiesis, which is maximal in ITP, minimal/absent in AA, and dysregulated in MDS. In ITP, the drug at 50-75 mg daily induced up to 85% responses both in clinical trials and real-life studies, with the possibility of tapering and discontinuation. In AA, eltrombopag at 150 mg daily was effective in about 40% of cases relapsed/refractory to standard immunosuppression or ineligible for bone marrow transplant. In MDS, the drug seems less effective, with responses in about a quarter of patients at various schedules. The efficacy of eltrombopag in ITP, AA, and MDS suggests the existence of common immune-pathological mechanisms in these diseases, including autoimmunity against peripheral blood cells and bone marrow precursors, as well as a possible evolution of one condition into the other. Additional mechanisms of action emerging from the clinical use of eltrombopag include modulation of T-regulatory cells, restoration of Fc-γ receptor balance in phagocytes, and an iron-mobilizing effect. In this review, we analyzed the most recent literature on eltrombopag use and efficacy in patients with ITP, AA, and MDS, exploring the basis for different dosing, combined treatments, and discontinuation in each context.


Assuntos
Anemia Aplástica/tratamento farmacológico , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Megacariócitos/imunologia , Síndromes Mielodisplásicas/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Imunomodulação , Imunossupressão , Púrpura Trombocitopênica Idiopática/imunologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Receptores de Trombopoetina/agonistas
8.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232025

RESUMO

BACKGROUND: The diagnostic and prognostic role of Th-1 chemokine receptor and Th-2 chemokine receptor in patients with primary immune thrombocytopenia has not been investigated extensively so far. In this study, our goal is to explore the diagnostic and prognostic role of C-C chemokine receptor 3 (CCR3) and C-C chemokine receptor 5 (CCR5) in patients with primary immune thrombocytopenia. METHODS: The expression levels of CCR3 and CCR5 were measured in peripheral blood mononuclear cells of pa-tients with primary immune thrombocytopenia and healthy subjects. The relationship between the expression levels of CCR3 and CCR5 and clinicopathological characteristics was analyzed. The diagnostic accuracy of CCR3 and CCR5 as biomarkers to discriminate primary immune thrombocytopenia patients from healthy subjects was determined. Univariate and multivariate Cox regression analysis were performed to determine the prognosis value of CCR3 and CCR5 in primary immune thrombocytopenia. The outcome of primary immune thrombocytopenia patients was also evaluated. RESULTS: Compared to healthy subjects, the expression level of CCR3 was significantly downregulated and CCR5 was significantly upregulated (p < 0.05). The expression levels of CCR3 and CCR5 were significantly correlated with bleeding times and platelet counts at diagnosis (p < 0.05). CCR3 and CCR5 could act as a suitable biomarker for differentiating the primary immune thrombocytopenia patients from healthy subjects. CCR3 and CCR5 were independent prognostic factors. Overexpression of CCR5 and low expression of CCR3 lead to poor clinical benefits and indicated poor prognosis of primary immune thrombocytopenia. CONCLUSIONS: To summarize, our results suggested that CCR3 and CCR5 could act as suitable biomarkers and indicated poor prognosis of primary immune thrombocytopenia.


Assuntos
Púrpura Trombocitopênica Idiopática/imunologia , Receptores CCR/imunologia , Células Th1/imunologia , Células Th2/imunologia , Biomarcadores/metabolismo , Quimiocinas CC/imunologia , Quimiocinas CC/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/metabolismo , Receptores CCR/metabolismo , Receptores CCR3/imunologia , Receptores CCR3/metabolismo , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
9.
Ann Hematol ; 98(8): 1845-1854, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154474

RESUMO

Primary immune thrombocytopenia is an autoimmune disease, characterized with decreased platelet and increased risk of bleeding. Recent studies have shown the reduction and dysfunction of regulatory T (Treg) cells in ITP patients. CD39 is highly expressed on the surface of Treg cells. It degrades ATP to AMP and CD73 dephosphorylates AMP into adenosine. Then adenosine binds with adenosine receptor and suppresses immune response by activating Treg cells and inhibiting the release of inflammatory cytokines from effector T (Teff) cells. Adenosine receptor has several subtypes and adenosine A2A receptor (A2AR) plays a crucial role especially within lymphocytes. The CD39+ Treg cells and the expression of A2AR showed abnormality in some autoimmune disease. But knowledge of CD39+ Treg cells and A2AR which are crucial in the adenosine immunosuppressive pathway is still limited in ITP. Thirty-one adult patients with newly diagnosed ITP were enrolled in this study. CD39 and A2AR expression was measured by flow cytometry and RT-PCR. The function of CD39 was reflected by the change of ATP concentration detected by CellTiter-Glo Luminescent Cell Viability Assay. CD39 expression within CD4+CD25+ Treg cells in ITP patients was decreased compared to normal controls. After high-dose dexamethasone therapy, response (R) group showed increased CD39 expression within Treg cells while non-response (NR) group did not show any difference in contrast to those before treatment. The expression of A2AR in CD4+CD25- Teff and CD4+CD25+ Treg cells was both lower in ITP patients than that of normal controls. After therapy, CD4+CD25- Teff cells had higher A2AR expression while CD4+CD25+ Treg cells did not show any difference in comparison to that before treatment. The enzymatic activity of CD39 was damaged in ITP patients and improved after high-dose dexamethasone therapy. In ITP, there was not only numerical decrease but also impaired enzymatic activity in CD39+ Treg cells. After high-dose dexamethasone treatment, these two defects could be reversed. Our results also suggested that ITP patients had reduced A2AR expression in both CD4+CD25+ Treg cells and CD4+CD25- Teff cells. CD4+CD25- Teff cells had increased A2AR expression after treatment.


Assuntos
Apirase/genética , Dexametasona/uso terapêutico , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptor A2A de Adenosina/genética , Linfócitos T Reguladores/efeitos dos fármacos , Adenosina/imunologia , Adenosina/metabolismo , Trifosfato de Adenosina/imunologia , Trifosfato de Adenosina/metabolismo , Adulto , Idoso , Apirase/imunologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/enzimologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Receptor A2A de Adenosina/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/enzimologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia
10.
Thromb Res ; 180: 1-9, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146120

RESUMO

BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated bleeding disorder in children. Activated T cells have been shown to play important roles in ITP. The aims of this study were to evaluate whether these T cell activation markers could be used as indicators to differentiate ITP patients from controls, and to assess whether they could be used as predictors of IVIG response in ITP patients. METHODS: A cohort of 92 hospitalized ITP patients, 49 unrelated healthy children, and 48 thrombocytosis patients were enrolled in this retrospective study between February 2013 and September 2018. Expression of CD25, HLA-DR, and CD69 on the surfaces of CD4+ and CD8+ T cells were detected by flow cytometry. All statistical analyses were performed using SPSS 20.0 software. RESULTS: Compared to the healthy controls, ITP patients had higher percentages of CD4 + CD25+ T cells, CD4 + HLA-DR+ T cells, CD8 + HLA-DR+ T cells, and CD8 + CD69+ T cells. Compared to the thrombocytosis patients, ITP patients had higher percentages of CD4 + HLA-DR+ T cells and CD8 + HLA-DR+ T cells, and lower CD4 + CD69+ T cells and CD8 + CD69+ T cells. Platelet count at admission had a negative correlation with CD4 + CD25+ T cells in ITP. CD4 + CD69+ T cells were decreased in chronic compared to the newly diagnosed and persistent ITP patients. Activated T cell markers had no predictive value for IVIG response in ITP patients. CONCLUSIONS: T cell activation markers were excessively expressed in pediatric ITP, and those markers had no predictive value for IVIG response in ITP patients.


Assuntos
Ativação Linfocitária , Púrpura Trombocitopênica Idiopática/imunologia , Linfócitos T/imunologia , Adolescente , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos CD4/análise , Criança , Pré-Escolar , Doença Crônica , Feminino , Antígenos HLA-DR/análise , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Lectinas Tipo C/análise , Masculino , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Linfócitos T/patologia , Trombocitose/diagnóstico , Trombocitose/imunologia
11.
Int Immunopharmacol ; 73: 181-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102993

RESUMO

BACKGROUND: Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by the restrained production of new platelets and the persistent reduction of existing platelets. An imbalance between Th17 and Treg cells is associated with a decrease in platelets. However, few therapeutic strategies aim to modulate this imbalance between Th17 and Treg cells in ITP. METHODS: ITP patients and healthy controls were enrolled in this study. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of the aryl hydrocarbon receptor (AhR), cytochrome P450 family 1 member A1 (CYP1A1), RAR-related orphan receptor gamma t (ROR-γt) and forkhead-box P3 (Foxp3). ELISA was employed to measure the secretion of IL-17A, IL-22 and IL-10. Flow cytometry was used to assess the proportion of Th17 and Treg cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to measure cell viability. RESULTS: The proportion of Th17 cells and the secretion of the pro-inflammatory cytokines IL-17A and IL-22 were both elevated, whereas the proportion of Treg cells and the production of the anti-inflammatory cytokine IL-10 were both reduced in ITP patients compared to healthy controls. The ratio of Th17/Treg cells and the expression of IL-17A and IL-22 displayed a positive correlation with the severity of ITP. Low and moderate concentrations of resveratrol did not affect the viability of CD4+ T cells from ITP patients but repressed Th17 differentiation and promoted Treg differentiation. Moreover, resveratrol could markedly downregulate the production of IL-17A and IL-22 and upregulate the secretion of IL-10 in CD4+ T cells in a time- and concentration-dependent manner. Mechanistic studies revealed that resveratrol exerted its beneficial function mainly through suppressing the AhR pathway, which led to the impaired expression of ROR-γt and reduced secretion of IL-17A and IL-22, as well as enhanced expression of Foxp3 and augmented secretion of IL-10. The induction of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in CD4+ T cells led to a Th17/Treg imbalance and the upregulation of IL-17A and IL-22, an effect that could be reversed by resveratrol treatment. CONCLUSION: This study revealed that resveratrol reversed the Th17/Treg imbalance by a mechanism involving the suppression of the AhR pathway. Since ITP is characterized by a Th17/Treg imbalance, resveratrol might be beneficial for the treatment of this condition.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Resveratrol/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adolescente , Adulto , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Resveratrol/farmacologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto Jovem
12.
Int J Lab Hematol ; 41 Suppl 1: 15-25, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069988

RESUMO

Heparin-induced thrombocytopenia (HIT) is a clinical-pathological disorder; thus, laboratory testing for the pathogenic platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies is central for diagnosis. The "iceberg" model summarizes the inter-relationship between platelet activation assays and PF4-dependent immunoassays, with platelet-activating antibodies comprising a subset of anti-PF4/heparin antibodies. The platelet serotonin-release assay (SRA), performed by reference laboratories, has high sensitivity and specificity for HIT (~95% each), and is especially suited for detecting highly pathogenic HIT sera containing both heparin-dependent and heparin-independent platelet-activating antibodies; this latter subgroup of antibodies explains "autoimmune HIT" disorders (delayed-onset, persisting, spontaneous, heparin "flush," fondaparinux-associated). Recently, SRA-negative HIT has become recognized, in which serum from some HIT patients contains subthreshold levels of platelet-activating antibodies (by SRA) that become detectable using a PF4-enhanced platelet activation assay. Unusual immunologic features of HIT include early antibody detectability (at onset of platelet count fall) and antibody transience (seroreversion). Widely available PF4-dependent enzyme immunoassays (EIAs) have high sensitivity but poor specificity for HIT, although specificity is enhanced with IgG-specific EIAs and strong positive results; unfortunately, EIA results are usually not available in real time. Automated rapid immunoassays, such as the chemiluminescence immunoassay (CLIA) and latex immunoturbidimetric assay (LIA), facilitate real-time laboratory diagnosis. Recently available likelihood ratio (LR) data for positive (LR+) and negative (LR-) test results allow clinicians to adjust their pretest probabilities for HIT, using Bayesian analysis, into real-time posttest probabilities that are dramatically increased (test positive) or decreased (test negative). Moreover, (semi-)quantitative CLIA- and LIA-positive results (weak, moderate, strong positive) can further refine the posttest probability of HIT.


Assuntos
Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/diagnóstico , Anticoagulantes/uso terapêutico , Autoanticorpos/imunologia , Técnicas de Laboratório Clínico , Heparina/uso terapêutico , Humanos , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/imunologia , Fator Plaquetário 4/antagonistas & inibidores , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/imunologia
13.
Int Immunopharmacol ; 72: 437-444, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31030100

RESUMO

BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated acquired autoimmune hemorrhagic disease. About one-third of patients are unresponsive to first-line therapies. Thalidomide (THD) as an immunomodulatory agent is now used to treat several autoimmune disorders. Therefore, we assessed the safety and efficacy of THD in corticosteroid-resistant or relapsed ITP patients, and preliminarily explore its mechanism. METHODS: 50 newly-diagnosed ITP patients and 47 healthy volunteers were enrolled in this study. Additionally, 17 corticosteroid-resistant or relapsed ITP patients were recruited, with 7 cases in the rhTPO + THD group and 10 cases in the THD monotherapy group. Overall response rate at 6, 12, and 24 months were assessed. Levels of Neuropilin-1(NRP-1), regulatory T cells (Tregs) and regulatory B cells (Bregs) were detected. RESULTS: Expression of NRP-1, Tregs and Bregs were reduced in newly-diagnosed ITP patients. In vitro, THD treatment upregulated expression of NRP-1and Tregs only in ITP patients. As for corticosteroid-resistant or relapsed ITP patients, overall response rate at 6, 12, and 24 months was 85.7%, 57.1% and 100% in the rhTPO + THD group and 60%, 75% and 83.3% in the THD group, respectively. Additionally, rhTPO plus THD or THD therapy significantly increased the levels of NRP-1, Tregs and Bregs in responders. CONCLUSIONS: Our study shows for the first time that NRP-1 is involved in the pathogenesis of ITP, THD could induce response in ITP patients by upregulating NRP-1 expression and restoring the proportion of Tregs and Bregs. THD might be served as a novel therapeutic agent in corticosteroid-resistant or relapsed ITP patients.


Assuntos
Imunossupressores/uso terapêutico , Neuropilina-1/imunologia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Talidomida/uso terapêutico , Adolescente , Corticosteroides/uso terapêutico , Adulto , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos B Reguladores/imunologia , Resistência a Medicamentos , Feminino , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Neuropilina-1/genética , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Talidomida/farmacologia , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
14.
J Immunol Res ; 2019: 6804806, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944836

RESUMO

Background: OX40, which is also known as tumor necrosis factor receptor superfamily member 4 (TNFRSF4), and its ligand (OX40L) play a critical role in the pathogenesis of autoimmune diseases. Immune thrombocytopenia (ITP), a hemorrhagic autoimmune disorder, is characterized by low platelet counts that are predominantly caused by antiplatelet autoantibodies. In this study, we firstly investigated the clinical significance of OX40 and OX40L expression in the pathogenesis of ITP in patients. Methods: Fifty-four newly diagnosed ITP patients and 24 healthy controls (HCs) were enrolled in this study. The percentage of OX40+CD4+T cells among CD4+T cells was analyzed by flow cytometry, and the expression levels of OX40 and OX40L mRNA were analyzed by quantitative real-time PCR. Plasma soluble OX40L (sOX40L) levels were analyzed by ELISA, and plasma levels of antiplatelet autoantibodies were analyzed by a solid-phase technique. Results: Compared with HCs, the frequencies of OX40+CD4+T cells were significantly increased in ITP patients, particularly in patients with positive antiplatelet autoantibodies compared to those with negative antiplatelet autoantibodies. The elevated frequencies of OX40+CD4+T cells were negatively correlated with low platelet counts in patients with positive antiplatelet autoantibodies. Plasma sOX40L levels in ITP patients were significantly greater than those in HCs and increased in patients with positive antiplatelet autoantibodies compared to those with negative antiplatelet autoantibodies. Plasma sOX40L levels were negatively correlated with low platelet counts in patients with positive antiplatelet autoantibodies. Additionally, the mRNA expression levels of OX40 and OX40L in PBMCs from ITP patients were also notably greater than those from HCs, and the expression levels of OX40 and OX40L were significantly different in ITP patients with positive and negative antiplatelet autoantibodies. Conclusion: These data indicated that increased expression levels of OX40 and OX40L were involved in the pathogenesis of ITP, and OX40 and OX40L may be valuable therapeutic targets for ITP.


Assuntos
Ligante OX40/genética , Púrpura Trombocitopênica Idiopática/imunologia , Receptores OX40/genética , Adulto , Idoso , Autoanticorpos/sangue , Plaquetas/imunologia , Linfócitos T CD4-Positivos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Ligante OX40/sangue , Púrpura Trombocitopênica Idiopática/patologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores OX40/imunologia , Adulto Jovem
15.
Am J Health Syst Pharm ; 76(11): 789-794, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-30951590

RESUMO

PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety, dosing and administration, and place in therapy of fostamatinib, a novel spleen tyrosine kinase inhibitor for the treatment of adult immune thrombocytopenia that has had an insufficient response to a previous treatment are summarized. SUMMARY: Fostamatinib is an oral inhibitor of spleen tyrosine kinase that is expressed on hematopoietic cells and plays a key role in the accelerated destruction of platelets through Fc-receptor activation. Fostamatinib is indicated for the treatment of adults with immune thrombocytopenia that has had an insufficient response to a previous treatment. In 2 parallel, identically designed, placebo-controlled Phase III trials, patients with persistent and chronic immune thrombocytopenia treated with fostamatinib demonstrated clinically meaningful responses in platelet counts with lower rates of moderate and severe bleeding-related adverse events. Overall, fostamatinib therapy is generally well tolerated; the most common adverse events reported in clinical trials were diarrhea, nausea, hypertension, liver function test elevations, and infection. Being primarily metabolized through the CYP3A4 pathway, fostamatinib is subject to drug-drug interactions and concomitant administration with strong CYP3A4 inhibitors or inducers can affect fostamatinib exposure. CONCLUSION: Fostamatinib is a first-in-class spleen tyrosine kinase inhibitor approved for the treatment of adults with immune thrombocytopenia that has had an insufficient response to a previous treatment.


Assuntos
Plaquetas/efeitos dos fármacos , Oxazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Piridinas/farmacologia , Quinase Syk/antagonistas & inibidores , Administração Oral , Plaquetas/imunologia , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Oxazinas/uso terapêutico , Contagem de Plaquetas , Inibidores de Proteínas Quinases/uso terapêutico , Púrpura Trombocitopênica Idiopática/imunologia , Piridinas/uso terapêutico , Receptores Fc/imunologia , Receptores Fc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Quinase Syk/metabolismo , Resultado do Tratamento
16.
Int J Mol Sci ; 20(5)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823385

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, with a complex and unclear pathogenesis. The impaired immunosuppressive capacity of mesenchymal stromal cells in ITP patients (ITP-MSCs) might play a role in the development of the disease. Correcting the MSC defects could represent an alternative therapeutic approach for ITP. High-dose dexamethasone (HD-Dexa) is the mainstay of the ITP therapeutic regimen, although it has several side effects. We previously demonstrated a role for cannabinoid receptor 2 (CB2) as a mediator of anti-inflammatory and immunoregulatory properties of human MSCs. We analyzed the effects of CB2 stimulation, with the selective agonist JWH-133, and of Dexa alone and in combination on ITP-MSC survival and immunosuppressive capacity. We provided new insights into the pathogenesis of ITP, suggesting CB2 receptor involvement in the impairment of ITP-MSC function and confirming MSCs as responsive cellular targets of Dexa. Moreover, we demonstrated that CB2 stimulation and Dexa attenuate apoptosis, via Bcl2 signaling, and restore the immune-modulatory properties of MSCs derived from ITP patients. These data suggest the possibility of using Dexa in combination with JWH-133 in ITP, reducing its dose and side effects but maintaining its therapeutic benefits.


Assuntos
Anti-Inflamatórios/farmacologia , Canabinoides/farmacologia , Dexametasona/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Púrpura Trombocitopênica Idiopática/imunologia , Receptor CB2 de Canabinoide/agonistas , Apoptose , Células Cultivadas , Criança , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/imunologia
19.
Hematology ; 24(1): 290-299, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30661482

RESUMO

OBJECTIVES: The great majority of adult patients with immune thrombocytopenia (ITP) who fail to respond to first-line medication or who relapse following response require additional treatment. Although broad guidelines currently exist for second-line and subsequent therapies, none to date have been prescriptive. The purpose of this systematic review and network meta-analysis was to establish a clinically relevant ranking of the efficacy and safety of medications for adults (≥18 years old) with previously treated ITP. METHODS: Relevant publications from Medline, Embase, and the Cochrane database were searched from their inceptions through July 31, 2018. The primary outcome was the overall response (OR, defined as a platelet count ≥50 × 109/L at the end of treatment without rescue therapy), while the secondary endpoints included early response (ER; i.e. a platelet count ≥50 × 109/L at week 2 after initiation of treatment) and therapy-related severe adverse events (AEs). RESULTS: Thirteen randomized controlled trials (1,202 patients) were included in this study. According to pooled results, romiplostim appears to be the most suitable treatment in terms of OR, followed by avatrombopag, eltrombopag, fostamatinib, and rituximab. Avatrombopag produced more satisfactory outcomes than romiplostim, eltrombopag, and rituximab in terms of ER; severe AEs profiles were similar across all treatment arms. CONCLUSION: Romiplostim appears to be the best option for patients who fail to respond to prior treatment or relapse thereafter, while avatrombopag and eltrombopag are reasonable alternatives. Rituximab monotherapy is not recommended, as it produces the lowest OR and ER rates.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Oxazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Rituximab/uso terapêutico , Tiazóis/uso terapêutico , Tiofenos/uso terapêutico , Trombopoetina/uso terapêutico , Adulto , Humanos , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Thromb Haemost ; 119(3): 377-383, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30630213

RESUMO

Immune thrombocytopaenia (ITP) is the most common autoimmune bleeding disorder, where platelets are destroyed by auto-antibodies and/or cell-mediated mechanisms. To understand the pathogenesis of ITP and explore novel therapeutics, three types of animal models have been used: passive ITP, secondary ITP and platelet-induced ITP. However, the first two are not ideal for chronic ITP pathophysiology where both T cell and B cell play important roles in platelet destruction. The most efficient model to mimic chronic ITP is developed by Chow et al through transferring splenocytes from platelet-immune CD61-knockout (KO) mice into mice with severe combined immunodeficiency (SCID). However, placental defects are evident in 25% of CD61-KO females and post-natal haemorrhage does occur, reducing the survival rate of embryos and pups. Compared with CD61-KO mice, CD41-KO ones do not present such problems. In our study, we employ CD41-KO mice as another source of immunized spleen cells. We evaluated our model with existing standards. Transferred SCID mice presented typical features of ITP, such as reduced platelet counts in the peripheral blood, increased anti-platelet antibody levels in the serum and reduced mature megakaryocytes in the bone marrow. What is more, lymphocyte-depletion experiments showed the role of CD8+ T cells in mature megakaryocyte decrease and thrombocytopaenia. And we confirmed the antibody-mediated platelet destruction by phagocytosis in the spleen. Our study develops another efficient murine ITP model through immunized CD41-KO mice.


Assuntos
Transferência Adotiva , Plaquetas/imunologia , Glicoproteína IIb da Membrana de Plaquetas/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Baço/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Plaquetas/metabolismo , Plaquetas/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Megacariócitos/imunologia , Megacariócitos/metabolismo , Megacariócitos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Fagocitose , Fenótipo , Glicoproteína IIb da Membrana de Plaquetas/genética , Glicoproteína IIb da Membrana de Plaquetas/metabolismo , Transfusão de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/metabolismo , Baço/metabolismo , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA