RESUMO
Acquired aplastic anemia (AA), a paradigm of bone marrow failure syndrome, is mainly caused by abnormal immune activation. The enhanced adipogenesis of bone marrow-derived mesenchymal stem cell (BM-MSC) results in a fatty marrow of AA. Leptin, an adipokine mainly generated by adipocytes, has powerful proinflammatory effects on immune cells and is associated with various autoimmune diseases. However, the role of leptin in the hyperimmune status of AA remains unknown. In this study, we firstly discovered the higher leptin concentration in AA-BM than that in healthy donors (HD)-BM and myelodysplastic syndrome (MDS)-BM. Then, we found AA-MSC could express high amounts of leptin during the process of adipogenesis. Compared with HD, the leptin receptor was also highly expressed on T cells in AA-BM. Furthermore, leptin significantly accelerated the proliferation and activation of T cells in AA-BM. And, leptin promoted the production of interferon-γby T cells in AA-BM. However, leptin remarkably inhibited the conversion of CD4+CD25- T cells into CD4+Foxp3+ T cells. Finally, we detected the cell signaling pathway in T cells from AA patients and found leptin could activate the STAT3 pathway. In summary, our data revealed the high expression of adipokine leptin in AA-BM which shaped a proinflammatory environment for T cells in AA-BM by activating the JAK2/STAT3 pathway.
Assuntos
Anemia Aplástica , Células-Tronco Mesenquimais , Anemia Aplástica/metabolismo , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Humanos , Leptina/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA.
Assuntos
Anemia Aplástica , Células Supressoras Mieloides , Humanos , Células Supressoras Mieloides/metabolismo , Arginase/genética , Anemia Aplástica/metabolismo , Diferenciação Celular , Imunossupressores , Sirolimo/farmacologiaRESUMO
Platelet transfusion refractoriness (PTR) is a life threatening, intractable clinical issue suffered by some serious aplastic anemia (SAA) patients. Unlike immune thrombocytopenia, effective treatments for PTR remain largely unknown. In our clinical work, we noted that PTR in some SAA patients could be rapidly relieved with the application of anti-thymocyte globulin (ATG), therefore, we retrospectively analyzed its management and outcomes for PTR in SAA patients. A cohort including 29 SAA with PTR patients who received ATG administration was enrolled in this study. All patients suffered from PTR before ATG administration. Among the 29 PTR patients treated with ATG, 21 (72.4.0 %) patients had response, importantly, 13 (44.8 %) patients had an immediately response following the first dose of ATG administration. Bleeding events of grade 3 or above occurred in 23 patients (79.3 %). With the recovery of effective platelet transfusion, the bleeding events in responders could be quickly relieved. The non-responders suffered from aggravated bleeding, including intracranial bleeding in two non-responders, which appeared on eighth and 29th days after ATG administration. Our study indicated that ATG was an effective and safe intervention in the management of PTR in SAA patients.
Assuntos
Anemia Aplástica , Trombocitopenia , Anemia Aplástica/terapia , Soro Antilinfocitário/uso terapêutico , Humanos , Transfusão de Plaquetas , Estudos Retrospectivos , Trombocitopenia/tratamento farmacológico , Resultado do TratamentoRESUMO
Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) have been widely accepted as the standard first-line treatments for severe aplastic anemia (SAA). However, most of the patients with SAA had a slim chance to access these strategies in developing countries. Here, we reported 10-year results in a cohort of 232 patients with SAA who received a novel IST of CsA, levamisole, and danazol (CsA&LMS-based regimen). The cumulative incidence of response was 52.1% at 6 months, 66.4% at 12 months, and 77.1% at 24 months. The 10-year overall survival (OS) and failure-free survival was 60.2% and 48.3%, respectively. Positive predictors of OS in multivariate analysis were higher pretreatment ANC, younger age, higher pretreatment absolute reticulocyte count (ARC), and response within 6 months. The probability of CsA&LMS discontinuation was 50.2% at 10 years. With a slow CsA&LMS taper, the actuarial risk for relapse was only 9.5%. The cumulative incidence of MDS/AML was 8.2% at 10 years. The long-term follow-up information demonstrated that the CsA&LMS regimen could be a promising strategy for patients with SAA in developing countries.
Assuntos
Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Ciclosporina/administração & dosagem , Terapia de Imunossupressão , Levamisol/administração & dosagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Países em Desenvolvimento , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxa de SobrevidaRESUMO
Immune-mediated quantitative and qualitative defects of hematopoietic stem/progenitor cells (HSPCs) play a vital role in the pathophysiology of acquired aplastic anemia (AA). Autophagy is closely related to T cell pathophysiology and the destiny of HSPCs, in which autophagy-related gene 5 (ATG5) is indispensably involved. We hypothesized that genetic variants of ATG5 might contribute to AA. We studied six ATG5 polymorphisms in a Chinese cohort of 176 patients with AA to compare with 157 healthy controls. A markedly decreased risk of AA in the recessive models of rs510432 and rs803360 polymorphisms (adjusted odds ratio [OR], 95% confidence interval [CI] = 0.467 [0.236-0.924], P = 0.029 for ATG5 rs510432; adjusted OR [95% CI] = 0.499 [0.255-0.975], P = 0.042 for ATG5 rs803360) was observed. Furthermore, the decreased risk was even more pronounced among nonsevere AA compared with healthy controls under recessive models (adjusted OR [95% CI] = 0.356 [0.141-0.901], P = 0.029 for ATG5 rs510432; adjusted OR [95% CI] = 0.348 [0.138-0.878], P = 0.025 for ATG5 rs803360; adjusted OR [95% CI] = 0.352 [0.139-0.891], P = 0.027 for ATG5 rs473543). Above all, rs573775 can strongly predict the occurrence of newly onset hematological event in patients with AA. Our results indicate that genetic ATG5 variants contributed to AA, which may facilitate further clarifying the underlying mechanisms of AA and making a patient-tailored medical decision.
RESUMO
As a type of congenital microcytic hypochromic anemia, thalassemia trait is often confused with other conditions, such as congenital sideroblastic anemia (CSA) and iron deficiency anemia, before a specific work-up is performed. However, these tests, including hemoglobin (Hb) electrophoresis, gene mutations and Prussian blue staining after bone marrow aspirate, are relatively expensive, time-consuming and invasive. To find labor-saving parameters to facilitate differential diagnosis, we retrospectively analyzed the routine blood indexes of 59 thalassemia trait cases [22 α-thalassemia (α-thal), 36 ß-thalassemia (ß-thal) and one α/ß-thal], 21 CSA patients, and 238 iron deficiency anemia controls. Significantly higher reticulocyte Hb equivalent (Ret-He) and lower red blood cell (RBC) distribution width (RDW) were prominent in thalassemia trait. Furthermore, RDW-standard deviation (SD) was independent of the severity of anemia in thalassemia trait, similar to Ret-He in CSA. In the context of the same grades of anemia, Ret-He combined with RDW was powerful in differentiation of thalassemia from CSA and iron deficiency anemia. By receiver operation curve (ROC) analysis, Ret-He had a specificity of 67.06% and a sensitivity of 76.92% with a cutoff value of 20.9 pg for thalassemia trait in mild anemia and a specificity of 84.09% and a sensitivity of 68.42% with a cutoff value of 19.1 pg for thalassemia trait in moderate anemia. Regarding CSA, Ret-He had 92.94% specificity and 60.00% sensitivity in mild anemia, with a cutoff value of 18.1 pg. Overall, Ret-He and RDW are two convenient indexes able to differentiate thalassemia from the other two microcytic anemias, CSA and iron deficiency anemia.
Assuntos
Índices de Eritrócitos , Hemoglobinas , Reticulócitos , Talassemia/diagnóstico , Anemia Ferropriva/diagnóstico , Anemia Sideroblástica/diagnóstico , Diagnóstico Diferencial , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Masculino , Estudos Retrospectivos , Talassemia/sangueRESUMO
CXCL10/IFN-γ-induced protein 10 (IP-10) and its corresponding receptor CXCR3 have long been considered to be involved in the pathophysiology of type 1 T (Th1) cell-orientated autoimmune diseases. However, the exact role of CXCL10 in the pathogenesis of aplastic anaemia (AA) has not been thoroughly studied. The aim of our study was to evaluate the plasma level of CXCL10 and its effects on CD4+ T cell differentiation in AA. In our study, we found that an elevated plasma level of CXCL10 was negatively correlated with platelet, absolute neutrophil and reticulocyte counts, while it was positively correlated with the proportion of lymphocytes in white blood cells in AA patients. To confirm the pro-inflammatory effects of CXCL10 in AA, we isolated CD4+ T cells and evaluated the function of CXCL10 in CD4+ T cell differentiation. In vitro stimulation experiments further revealed the pro-inflammatory role of CXCL10 in AA, partially by promoting the secretion of interferon (IFN)-γ and IL-17. In addition, CXCL10 significantly skewed CD4+ T cell differentiation to Th1 cells and T helper 17 (Th17) cells in AA patients, while it inhibited the differentiation of type 2 T (Th2) cells only in controls. The mRNA expression of transcription factors representative of T cell differentiation was detected by RT-PCR. Consistently, our results showed that after CXCL10 treatment, the expression of T-bet and RORγt was significantly enhanced, while the expression of GATA3 was inhibited. In conclusion, our results indicated that CXCL10, a pro-inflammatory chemokine, might be involved in the abnormal immune response in AA.
Assuntos
Anemia Aplástica/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/farmacologia , Células Th1/imunologia , Adulto , Anemia Aplástica/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Quimiocina CXCL10/sangue , Quimiocina CXCL10/genética , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Humanos , Inflamação , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-17/sangue , Masculino , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/efeitos dos fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/fisiologiaRESUMO
Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2 D3 ], the biologically active metabolite of vitamin D, is a critical modulator of immune response via binding with vitamin D receptor (VDR). Previous studies have established that 1,25(OH)2 D3 and VDR were involved in the pathogenesis of some autoimmune diseases. In this study, we evaluated the involvement of 1,25(OH)2 D3 and VDR on T-cell responses in AA. Plasma 25(OH)D3 levels were comparable between patients with AA and healthy controls. Surprisingly, VDR mRNA was significantly lower in untreated patients with AA than in healthy controls. Subsequent in vitro experiments revealed that 1,25(OH)2 D3 treatment suppressed the proliferation of lymphocytes and inhibited the secretion of interferon-γ, tumor necrosis factor-α, and interleukin-17A, meanwhile promoting the production of transforming growth factor-ß1 in patients with AA. Moreover, 1,25(OH)2 D3 inhibited the differentiation of type 1 and Th17 cells but induced the differentiation of type 2 and regulatory T cells. Interestingly, VDR mRNA was elevated in healthy controls after 1,25(OH)2 D3 treatment, but not in patients with AA. In conclusion, decreased expression of VDR might contribute to the hyperimmune status of AA and appropriate vitamin D supplementation could partly correct the immune dysfunction by strengthening signal transduction through VDR in patients with AA.
Assuntos
Anemia Aplástica/genética , Anemia Aplástica/imunologia , Regulação da Expressão Gênica , Imunidade/genética , Receptores de Calcitriol/genética , Adulto , Anemia Aplástica/metabolismo , Biomarcadores , Calcitriol/sangue , Calcitriol/metabolismo , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Citocinas/biossíntese , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunomodulação , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Calcitriol/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto JovemRESUMO
Acquired aplastic anemia (AA) is an immune mediated bone marrow failure syndrome which is associated with impaired T-cell immune responses. In this work we investigated the role of Th17 immune response in AA. Our results showed that the absolute numbers of circulating IL-17-producing CD4(+) T cells and CD4(+)CD161(+)CCR6(+) cells, the blood plasma level of IL-17, and the expression level of Th17 lineage-specifying transcription factor RORC in circulating CD4(+) T cells, were not increased in AA. These results suggest that Th17 immune response may not play an important role in the pathogenesis of AA.
Assuntos
Anemia Aplástica/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Adulto , Anemia Aplástica/sangue , Anemia Aplástica/patologia , Feminino , Humanos , Interleucina-17/sangue , Masculino , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/sangue , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Células Th17/metabolismo , Células Th17/patologiaRESUMO
Interleukin (IL)-35 is a novel regulatory cytokine primarily produced by regulatory T cells. Accumulating evidence has established that IL-35 plays an important role in the regulation of immune homeostasis, but little is known regarding the function of IL-35 in acquired aplastic anemia (AA). The aim of the present study was to investigate the expression of IL-35 and its effects on T cell response in AA. Our study demonstrated that significantly decreased plasma levels of IL-35 in AA were closely correlated with disease severity. In vitro stimulation experiment further confirmed the anti-inflammatory effects of IL-35, including suppressing the proliferation of CD4(+) and CD8(+) effector T cells, inhibiting the secretion of interferon-γ, tumor necrosis factor-α and IL-17 and promoting the production of transforming growth factor-ß by peripheral blood mononuclear cells from patients with AA. Furthermore, we established that IL-35 inhibited the differentiation of type 1 T cells and T helper 17 cells but promoted the differentiation of type 2 T cells. Accordingly, the expression of T-bet and RORγt was inhibited while the expression of GATA3 was induced after IL-35 treatment. In summary, our findings suggested that decreased IL-35 might contribute to the loss of immune-tolerance and be critically involved in the pathogenesis of AA.
Assuntos
Anemia Aplástica/fisiopatologia , Inflamação/fisiopatologia , Interleucinas/fisiologia , Adulto , Estudos de Casos e Controles , Proliferação de Células/fisiologia , Citocinas/metabolismo , Feminino , Humanos , Interleucinas/sangue , Interleucinas/genética , Masculino , Monócitos/metabolismo , RNA Mensageiro/genéticaRESUMO
OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children. To characterize the clinical presentations and survival, we performed a retrospective analysis of pediatric patients. METHODS: We reviewed 55 pediatric patients with PNH referred to our hospital from January 1990 through June 2012 to assess clinical presentations, survival, and differences among subcategories. RESULTS: The overall survival 10 years after diagnosis estimated via the Kaplan-Meier method was 77.6%. The cohort of patients was divided into subcategories of classic PNH, PNH/aplastic anemia (AA), and subclinical PNH (PNH-sc)/AA based on the recently proposed PNH working clinical classification. We found that patients with classic PNH and PNH/AA had larger PNH clones and many more parameters of hemolysis, but patients with PNH-sc/AA had smaller PNH clones, fewer parameters of hemolysis, and a higher rate of bone marrow failure. Our results revealed a high rate of bone marrow failure and a low rate of hemoglobinuria at presentation. Furthermore, thrombotic events were not observed in our patients, which is significantly different from the rate seen in Caucasian patients. Additionally, pediatric patients with PNH may develop bone marrow cytogenetic abnormalities. CONCLUSION: This study provides insight into Chinese pediatric PNH patients and may aid in setting up individualized therapeutic regimens.
Assuntos
Hemoglobinúria Paroxística , Hemólise , Adolescente , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Criança , China , Intervalo Livre de Doença , Feminino , Seguimentos , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/etiologia , Hemoglobinúria Paroxística/mortalidade , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/fisiopatologia , Humanos , Masculino , Taxa de SobrevidaRESUMO
Clinical and experimental evidence suggests an immune-mediated pathophysiology in subjects with lower-risk myelodysplastic syndromes (MDS) in whom immunosuppressive therapy may be effective. The novel immunosuppressive strategy of cyclosporine A (CsA) alternately combined with levamisole (LMS; CsA + LMS regimen) can dramatically improve the response rate and survival in aplastic anemia from those of our previous study. Herein, we retrospectively analyzed the data of 89 lower-risk MDS patients who received the CsA + LMS regimen. A total of 63 patients (70.8%) achieved either complete remission or hematological improvement at 4 months. Overall, 51, 41 and 19 patients had erythroid, platelet and neutrophil responses, respectively. Following the CsA + LMS regimen, 6 patients progressed to more advanced MDS at a median interval of 5 months (range, 3-42 months). The estimated 24-month progression-free survival was 82.2% (95% CI, 72.84-91.56) for all patients. Within the median follow-up of 18.5 months (range, 7.0-61.0), 6 patients died. In conclusion, the CsA + LMS regimen alleviated cytopenias and improved survival and freedom from evolution, suggesting that it could be reserved as an alternative choice for lower-risk MDS.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Ciclosporina/administração & dosagem , Levamisol/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Criança , Ciclosporina/efeitos adversos , Progressão da Doença , Feminino , Humanos , Levamisol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure attacked by autoreactive effector T cells and BM is the main target organ. CD4(+)CD25(+) regulatory T cells (Tregs) were believed to control development and progression of autoimmunity by suppressing autoreactive effector T cells, but little was known regarding the function of Tregs in AA. Our study demonstrated that both peripheral blood (PB) and BM had decreased frequencies of Tregs, accompanied with a reversed lower ratio of Treg frequencies between BM and PB in AA. PB Tregs in AA had impaired migratory ability because of lower CXCR4 (but not for CXCR7) expression. Interestingly, we first showed that impairment of Treg-mediated immunosuppression was intrinsic to Tregs, rather than resistance of effector T cells to suppression in AA by coculture assays and criss-cross experiments in vitro. Furthermore, Tregs in AA were less able to inhibit interferon-γ production by effector T cells. Defective immunosuppression by Tregs could contribute to impaired hematopoiesis conducted by effector T cells in vitro. Our study provided powerful evidence that impairment of Tregs played a critical role in the pathophysiology of AA. Thus, patients with AA might greatly benefit from a Treg-oriented immunosuppressive strategy.
Assuntos
Anemia Aplástica/imunologia , Linfócitos T CD4-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Anemia Aplástica/genética , Anemia Aplástica/patologia , Medula Óssea/imunologia , Medula Óssea/patologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular , Feminino , Regulação da Expressão Gênica , Hematopoese , Humanos , Terapia de Imunossupressão , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR/genética , Receptores CXCR4/genética , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Adulto JovemRESUMO
Congenital dyserythropoietic anemias (CDAs) are a group of hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts in the bone marrow. Most cases of CDA, caused by a wide spectrum of mutations, have been reported from Europe and Mediterranean countries, while a few cases have been described in China. Here, we present three cases of CDA, one from one family and two from a second unrelated family, with typical morphologic features and clinical presentations. Sequence analysis of CDA-related genes revealed that the proband with CDA Ι in the first family was a compound heterozygote of CDAN1 with mutation IVS-12+2T>C and c. 3389C>T, while both probands with CDA ΙΙ in the second family were a homozygote of the SEC23B gene with mutation c.938G>A (R313H). This study suggests that more patients with CDA, sharing a phenotype and genetic background like those of European and Mediterranean origin, remain to be diagnosed and reported in China.
Assuntos
Anemia Diseritropoética Congênita/genética , Eritroblastos/metabolismo , Eritropoese , Glicoproteínas/genética , Proteínas de Transporte Vesicular/genética , Adulto , Anemia Diseritropoética Congênita/classificação , Anemia Diseritropoética Congênita/etnologia , Anemia Diseritropoética Congênita/patologia , Povo Asiático , Sequência de Bases , Eritroblastos/patologia , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Proteínas Nucleares , Linhagem , FenótipoRESUMO
To explore the predictive value of thyroid function in severe aplastic anemia (SAA) patients treated with immunosuppressive therapy (IST), 149 SAA patients in our center were enrolled between February 2015 and June 2020 in this study. We assessed the thyroid function of 134 patients without primary thyroid diseases, and discovered that 89 patients were accompanied by abnormal thyroid hormone, especially low triiodothyronine (T3). Patients with higher pretreatment-free T3 (FT3) levels (>5 pmol/L) demonstrated superior response rates at 3 and 6 months after IST compared to those with lower FT3 levels (54.5% vs 35.4%, P = .020; 67.3% vs 46.9%, P = .020). Multivariate analysis indicated that shorter disease duration (≤56 days) and response at 6 months were independent favorable factors of overall survival (relative risk [RR] = 2.66, 95% confidence interval [CI] = 1.03-6.90, P = .040; RR = 30.10, 95% CI = 4.02-225.66, P = .001). The 6-year failure-free survival (FFS) was 53.8% (95% CI = 40.9%-65.1%). Multivariate analysis revealed that patients with a response at 6 months, shorter duration (≤56 days) and receiving rabbit antithymocyte globulin (ATG) had better FFS outcomes than those without a response at 6 months, with a longer duration and receiving porcine ATG (RR = 22.6, 95% CI = 7.9-64.9, P < .001; RR = 2.4, 95% CI = 1.3-4.5, P = .006; RR = 2.5, 95% CI = 1.1-5.8, P = .030). In conclusion, FT3 levels reflect the severity of SAA, and patients with higher FT3 levels (>5 pmol/L) had superior response rates than those with lower ones.
RESUMO
The appropriate management of patients with moderate aplastic anemia (mAA) remains to be unclear and controversial. A cohort of 118 patients with mAA received a novel immunosuppressive strategy of cyclosporine alternately combined with levamisole (CSA and LMS regimen), which included 42 newly diagnosed and 76 chronic (disease duration >6 months) cases. CSA and LMS regimen was orally administrated with the initial dose of CSA 3 mg/kg per day in adults or 5 mg/kg per day in children, and LMS 150 mg per day in adults or 2.5 mg/kg per day in children, continued for 12 more months after achieving maximal hematologic response, followed by a slow tapering. The overall response rates were of 100 and 86.8 % for newly diagnosed and chronic group, respectively. The 24-month progression-free survival were 95.2 % (95 % confidence intervals [CI], 85.9-100 %) and 93.6 % (95 % CI, 86.9-100 %) for newly diagnosed and chronic group, respectively (P = 0.50). The 2-year event-free survival for the patients in newly diagnosed group (86.6 %; 95 % CI, 70.4-100 %) was superior to that in chronic group (57.0 %; 95 % CI, 43.5-70.4 %, P = 0.001). To date, 11 patients relapsed and no patients evolved to clonal disorders. Thus, CSA and LMS regimen represents a promising immunosuppressive strategy for mAA.
Assuntos
Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Imunossupressores/administração & dosagem , Levamisol/administração & dosagem , Adolescente , Adulto , Anemia Aplástica/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto JovemRESUMO
Background: Activated cytotoxic T cells (CTLs) recognize the auto-antigens presented on hematopoietic stem/progenitor cells (HSPCs) through class I human leukocyte antigen (HLA) molecules and play an important role in the immune pathogenesis of aplastic anemia (AA). Previous reports demonstrated that HLA was related to the disease susceptibility and response to immunosuppressive therapy (IST) in AA patients. Recent studies have indicated that specific HLA allele deletions, which helped AA patients to evade CTL-driven autoimmune responses and escape from immune surveillance, may lead to high-risk clonal evolution. Therefore, HLA genotyping has a particular predictive value for the response to IST and the risk of clonal evolution. However, there are limited studies on this topic in the Chinese population. Methods: To explore the value of HLA genotyping in Chinese patients with AA, 95 AA patients treated with IST were retrospectively investigated. Results: The alleles HLA-B*15:18 and HLA-C*04:01 were associated with a superior long-term response to IST (P = 0.025; P = 0.027, respectively), while the allele HLA-B*40:01 indicated an inferior result (P = 0.02). The allele HLA-A*01:01 and HLA-B*54:01 were associated with high-risk clonal evolution (P = 0.032; P = 0.01, respectively), and the former had a higher frequency in very severe AA (VSAA) patients than that in severe AA (SAA) patients (12.7% vs 0%, P = 0.02). The HLA-DQ*03:03 and HLA-DR*09:01 alleles were associated with high-risk clonal evolution and poor long-term survival in patients aged ≥40 years. Such patients may be recommended for early allogeneic hematopoietic stem cell transplantation rather than the routine IST treatment. Conclusion: HLA genotype has crucial value in predicting the outcome of IST and long-term survival in AA patients, and thus may assist an individualized treatment strategy.
Assuntos
Anemia Aplástica , Humanos , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Estudos Retrospectivos , População do Leste Asiático , Imunossupressores/uso terapêutico , Resultado do Tratamento , Antígenos HLA/genética , Antígenos HLA-B/genéticaRESUMO
OBJECTIVE: To explore the difference of lymphocyte subsets in peripheral blood (PB) between aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (hypo-MDS) patients, meanwhile to compare the clinical parameters obtained from PB and bone marrow (BM). METHODS: The lymphocyte subsets in hypo-MDS (n=25) and AA (n=33) patients were investigated by flow cytometry. Meanwhile, the differences in PB cell counts, biochemical indicators, BM cell counts and abnormal chromosomes between the two groups were analyzed. RESULTS: The percentage of CD8+T cells in AA group was significantly higher than that in hypo-MDS group (P=0.001), while the percentage of CD4+ T cells and the CD4+/CD8+ ratio in AA group were obviously lower than those in hypo-MDS group (P=0.015 and 0.001, respectively). Furthermore, the proportion of CD4+ and CD8+ activated T (TA) cells, and memory Tregs in AA group was distinctly lower than those in hypo-MDS group (P=0.043, 0.015 and 0.024, respectively). Nevertheless, the percentage of CD8+ naive T (TN) cells in AA patients was remarkably higher (P=0.044). And hypo-MDS patients had declined lymphocyte counts (P=0.025), increased levels of total bilirubin (TBil), lactate dehydrogenase (LDH), vitamin B12 and proportion of BM blasts than AA patients (P=0.019, 0.023, 0.027 and 0.045, respectively). CONCLUSION: In this study it was confirmed that the percentages of CD4+ and CD8+ TA cells, memory Tregs and CD8+ TN cells were significantly different between AA and hypo-MDS patients, which provide an essential basis for the identification of these two diseases.
RESUMO
INTRODUCTION: Acquired aplastic anemia (AA), a heterogeneous bone marrow (BM) failure disease, is mainly mediated by the immune destruction of hematopoietic stem cells (HSCs). Given the predominant role of immunosuppressive therapy (IST) in AA, it is sensible to theorize that variants of cytokine genes might affect the outcome of IST. METHODS: In this study, we analyzed three single nucleotide polymorphisms (SNPs) of interleukin (IL)-10 gene in promoter region to clarify their relationship with susceptibility, clinical efficacy and prognosis of AA. RESULTS: We observed that CT genotype of IL-10 rs1800896 was associated with a decreased risk of AA (adjusted OR = 0.541 [95% CI 0.295-0.993], p = .047). Besides, the disease severity differed considerably by IL-10 gene promoter genotypes and alleles. Furthermore, IL-10 SNPs influenced efficacy of IST, with unfavorable response exhibited by rs1800871 and rs1800872 in dominant models (GG + AG vs. AA, adjusted OR = 0.409 [95% CI 0.178-0.943, p = .036] for rs1800871 and GG + GT vs. TT, adjusted OR = 0.396 [95% CI 0.173-0.909, p = .028] for rs1800872, respectively). CONCLUSION: The polymorphisms of IL-10 promoter region were informatively genetic risk factors which might be conducive to the insights into the mechanisms of AA and the design of individual regimens.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Interleucina-10 , Pancitopenia , Humanos , Anemia Aplástica/genética , Anemia Aplástica/terapia , Estudos de Casos e Controles , População do Leste Asiático , Predisposição Genética para Doença , Genótipo , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
OBJECTIVE: To evaluate the expression level of melatonin and its effects on immune function in aplastic anemia (AA) patients. METHODS: The enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma levels of melatonin in AA patients, and the correlation between melatonin levels and laboratory indexs was analyzed. The activation, proliferation, and apoptosis of T cells from AA patients were analyzed by flow cytometry with or without melatonin in vitro. RESULTS: The plasma levels of melatonin in AA patients were significantly lower compared with healthy controls (HC) (12.23 pg/ml vs 20.04 pg/ml, P < 0.01), while the plasma melatonin levels of AA patients in remission group after immunosuppressive therapy (IST) were significantly higher than those in non-remission group (29.16 pg/ml vs 11.73 pg/ml, P =0.04). Moreover, the melatonin levels were positively correlated with platelets (r =0.49), the absolute reticulocyte count (r =0.45), and the percentage of neutrophils (r =0.43). Meanwhile, there was a negative correlation between melatonin levels and the percentages of lymphocytes (r =-0.45). The expressions of CD25 and CD69 in both CD4+ and CD8+ T cells from AA patients were remarkably inhibited by melatonin in vitro (all P < 0.05). When cultured with melatonin, the proliferation rates of both CD4+ and CD8+ T cells from AA patients were markedly suppressed (P =0.01 andP < 0.01). CONCLUSION: The plasma levels of melatonin were decreased in AA patients, which might play an important role in the mechanism of immunological abnormalities. The hyperimmune status of AA patients could be partially ameliorated by melatonin in vitro.