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1.
Medicine (Baltimore) ; 99(1): e18624, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31895820

RESUMEN

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.


Asunto(s)
Inmunoglobulinas Intravenosas/efectos adversos , Neutropenia/etiología , Púrpura Trombocitopénica Idiopática/terapia , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inmunología , Estudios Retrospectivos , Adulto Joven
2.
Medicine (Baltimore) ; 98(43): e17608, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31651870

RESUMEN

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.


Asunto(s)
Antígeno B7-H1/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Linfocitos T Reguladores/inmunología , Balance Th1 - Th2/fisiología , Células Th17/inmunología , Adulto , Antígenos CD28/inmunología , Complejo CD3/inmunología , Estudios de Casos y Controles , Citocinas/inmunología , Femenino , Humanos , Interferón gamma/metabolismo , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Fitohemaglutininas/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Púrpura Trombocitopénica Idiopática/sangre , Transducción de Señal/inmunología , Linfocitos T/inmunología , Balance Th1 - Th2/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo
3.
Biomed Res Int ; 2019: 1050285, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31380412

RESUMEN

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.


Asunto(s)
Factores Reguladores del Interferón/genética , Interleucina-10/genética , Púrpura Trombocitopénica Idiopática/genética , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Inmunosupresión/métodos , Factores Reguladores del Interferón/inmunología , Masculino , Persona de Mediana Edad , Unión Proteica/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/patología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
4.
Drugs ; 79(12): 1305-1319, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31292909

RESUMEN

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.


Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Megacariocitos/inmunología , Síndromes Mielodisplásicos/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Pirazoles/uso terapéutico , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Inmunomodulación , Inmunosupresión , Púrpura Trombocitopénica Idiopática/inmunología , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Receptores de Trombopoyetina/agonistas
5.
Chin J Integr Med ; 25(7): 483-489, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31278626

RESUMEN

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.


Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Inmunidad Celular , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/inmunología , Investigación , Hemorragia/tratamiento farmacológico , Humanos
6.
Ann Hematol ; 98(8): 1845-1854, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31154474

RESUMEN

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.


Asunto(s)
Apirasa/genética , Dexametasona/uso terapéutico , Inmunosupresores/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptor de Adenosina A2A/genética , Linfocitos T Reguladores/efectos de los fármacos , Adenosina/inmunología , Adenosina/metabolismo , Adenosina Trifosfato/inmunología , Adenosina Trifosfato/metabolismo , Adulto , Anciano , Apirasa/inmunología , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/enzimología , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/inmunología , Receptor de Adenosina A2A/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/enzimología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología
7.
Clin Lab ; 65(6)2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-31232025

RESUMEN

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.


Asunto(s)
Púrpura Trombocitopénica Idiopática/inmunología , Receptores CCR/inmunología , Células TH1/inmunología , Células Th2/inmunología , Biomarcadores/metabolismo , Quimiocinas CC/inmunología , Quimiocinas CC/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/metabolismo , Receptores CCR/metabolismo , Receptores CCR3/inmunología , Receptores CCR3/metabolismo , Receptores CCR5/inmunología , Receptores CCR5/metabolismo , Células TH1/metabolismo , Células Th2/metabolismo
8.
Int J Lab Hematol ; 41 Suppl 1: 15-25, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31069988

RESUMEN

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.


Asunto(s)
Anticoagulantes/efectos adversos , Heparina/efectos adversos , Púrpura Trombocitopénica Idiopática/inducido químicamente , Púrpura Trombocitopénica Idiopática/diagnóstico , Anticoagulantes/uso terapéutico , Autoanticuerpos/inmunología , Técnicas de Laboratorio Clínico , Heparina/uso terapéutico , Humanos , Activación Plaquetaria/efectos de los fármacos , Activación Plaquetaria/inmunología , Factor Plaquetario 4/antagonistas & inhibidores , Factor Plaquetario 4/inmunología , Púrpura Trombocitopénica Idiopática/inmunología
9.
Thromb Res ; 180: 1-9, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31146120

RESUMEN

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.


Asunto(s)
Activación de Linfocitos , Púrpura Trombocitopénica Idiopática/inmunología , Linfocitos T/inmunología , Adolescente , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Antígenos CD4/análisis , Niño , Preescolar , Enfermedad Crónica , Femenino , Antígenos HLA-DR/análisis , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Lactante , Lectinas Tipo C/análisis , Masculino , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/terapia , Linfocitos T/patología , Trombocitosis/diagnóstico , Trombocitosis/inmunología
10.
Int Immunopharmacol ; 73: 181-192, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31102993

RESUMEN

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.


Asunto(s)
Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Resveratrol/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Adolescente , Adulto , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/inmunología , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Resveratrol/farmacología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adulto Joven
11.
Int Immunopharmacol ; 72: 437-444, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31030100

RESUMEN

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.


Asunto(s)
Inmunosupresores/uso terapéutico , Neuropilina-1/inmunología , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Talidomida/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Linfocitos B Reguladores/efectos de los fármacos , Linfocitos B Reguladores/inmunología , Resistencia a Medicamentos , Femenino , Humanos , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Neuropilina-1/genética , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Talidomida/farmacología , Regulación hacia Arriba/efectos de los fármacos , Adulto Joven
12.
J Immunol Res ; 2019: 6804806, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30944836

RESUMEN

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.


Asunto(s)
Ligando OX40/genética , Púrpura Trombocitopénica Idiopática/inmunología , Receptores OX40/genética , Adulto , Anciano , Autoanticuerpos/sangre , Plaquetas/inmunología , Linfocitos T CD4-Positivos/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Ligando OX40/sangre , Púrpura Trombocitopénica Idiopática/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores OX40/inmunología , Adulto Joven
13.
Am J Health Syst Pharm ; 76(11): 789-794, 2019 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-30951590

RESUMEN

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.


Asunto(s)
Plaquetas/efectos de los fármacos , Oxazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Piridinas/farmacología , Quinasa Syk/antagonistas & inhibidores , Administración Oral , Plaquetas/inmunología , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Humanos , Oxazinas/uso terapéutico , Recuento de Plaquetas , Inhibidores de Proteínas Quinasas/uso terapéutico , Púrpura Trombocitopénica Idiopática/inmunología , Piridinas/uso terapéutico , Receptores Fc/inmunología , Receptores Fc/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Quinasa Syk/metabolismo , Resultado del Tratamiento
15.
Int J Mol Sci ; 20(5)2019 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-30823385

RESUMEN

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.


Asunto(s)
Antiinflamatorios/farmacología , Cannabinoides/farmacología , Dexametasona/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Púrpura Trombocitopénica Idiopática/inmunología , Receptor Cannabinoide CB2/agonistas , Apoptosis , Células Cultivadas , Niño , Femenino , Humanos , Masculino , Células Madre Mesenquimatosas/inmunología
16.
Thromb Haemost ; 119(3): 377-383, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30630213

RESUMEN

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.


Asunto(s)
Traslado Adoptivo , Plaquetas/inmunología , Glicoproteína IIb de Membrana Plaquetaria/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Bazo/inmunología , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Plaquetas/metabolismo , Plaquetas/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Megacariocitos/inmunología , Megacariocitos/metabolismo , Megacariocitos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Fagocitosis , Fenotipo , Glicoproteína IIb de Membrana Plaquetaria/genética , Glicoproteína IIb de Membrana Plaquetaria/metabolismo , Transfusión de Plaquetas , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/metabolismo , Bazo/metabolismo , Factores de Tiempo
17.
Hematology ; 24(1): 290-299, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30661482

RESUMEN

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.


Asunto(s)
Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Oxazinas/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Rituximab/uso terapéutico , Tiazoles/uso terapéutico , Tiofenos/uso terapéutico , Trombopoyetina/uso terapéutico , Adulto , Humanos , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/patología , Ensayos Clínicos Controlados Aleatorios como Asunto
19.
Pediatr Neonatol ; 60(4): 411-416, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30470618

RESUMEN

OBJECTIVE: Immune thrombocytopenic purpura (ITP) is the most common cause of acquired thrombocytopenia children. The aim of this retrospective study is to describe presenting features and clinical characteristics of ITP and evaluate clinical course, treatment modalities, and complications and determine the effects of preceding infection history, age, gender, treatment modality, and admission platelet count on chronicity. METHOD: Two hundred and eleven patients who were diagnosed ITP and followed-up in Department of Pediatric Hematology, Ankara Children Hematology Oncology Education and Research Hospital between January 2008 and September 2012 were included. Age of the patients, gender, date of admission, date of diagnosis, complaint in the application, previous infection and laboratory tests were recorded. RESULTS: Mean age of the patients on diagnosis was 5.4 ± 4.1 years. The female/male ratio was 1.03. The clinical courses were determined as acute or chronic in 72% and 28% of patients respectively. Mean age at diagnosis was significantly higher in chronic ITP (p < 0.01). Chronic course was significantly higher in female patients (p < 0.05). The most frequent complaint was bruises on the skin (68%). The most common physical examination findings were petechiae, purpura and ecchymosis (89%). Patients with a history of past infection (53.6%) and who had serologically positive infection (15.6%) frequently had acute course (p < 0.01). The most common serologically positive infection was Rubella. The mean platelet count was significantly higher in chronic ITP (p < 0.01). In the initial treatment of patients admitted in the acute phase, megadose methylprednisolone (MDMP) was used in 31% of patients, intravenous immune globulin (IVIG) in 55% of patients and anti-D in 2% of patients while 12% did not receive any treatment. There were no significant differences between the recurrence rate and treatment modality (p > 0.05). CONCLUSION: In our study, in females and in patients without any history of past infection, platelet count >20 × 109/L and initial diagnosis age > 10 years were found to increase the probability of chronic disease, which is compatible with the literature.


Asunto(s)
Glucocorticoides/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Metilprednisolona/uso terapéutico , Púrpura Trombocitopénica Idiopática/terapia , Globulina Inmune rho(D)/uso terapéutico , Factores de Edad , Niño , Preescolar , Enfermedad Crónica , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/inmunología , Progresión de la Enfermedad , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/inmunología , Femenino , Hospitalización , Humanos , Lactante , Masculino , Recuento de Plaquetas , Pronóstico , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/inmunología , Recurrencia , Estudios Retrospectivos , Rubéola (Sarampión Alemán)/epidemiología , Rubéola (Sarampión Alemán)/inmunología , Factores Sexuales , Turquia/epidemiología
20.
Scand J Immunol ; 89(3): e12739, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30506564

RESUMEN

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by autoantibody-mediated platelet destruction. Multiple factors have been implicated in ITP pathogenesis, including T-lymphocyte dysfunctions. Increasing studies have indicated that stem cell memory-like T cell (TSCM) plays an important role in the development of multiple autoimmune diseases. This study aimed to explore the clinical correlation between the TSCM subset and ITP. The percentages of peripheral blood naïve T cells (TNs), TSCMs, central memory T cells (TCMs), effector memory T cells (TEMs) and effector T cells (TEs) among CD4+ and CD8+ T cells in 20 ITP patients before and after treatment were detected using flow cytometry. Our results showed that the percentages of peripheral blood CD4+ and CD8+ T cells in ITP patients were imbalanced. The percentage of CD8+ TSCMs in peripheral blood before treatment in ITP patients was significantly higher than that in healthy controls, whereas the percentages of the other T cell subsets did not exhibit significant differences. Our study further analysed the correlation between the change in the percentage of CD8+ TSCMs and the treatment efficacy. The results showed that the percentage of peripheral blood CD8+ TSCMs in ITP patients after glucocorticoid treatment significantly decreased and the changes of the percentages of CD8+ TSCMs before and after treatment in complete response (CR) and response (R) patients were obvious. Our finding showed that the imbalance of the percentage of CD8+ TSCMs might be involved in the development of ITP and might serve as a novel indicator of efficacy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Células Precursoras de Linfocitos T/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad
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