RESUMO
Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by normocytic normochromic anemia with severe reticulocytopenia and absence of erythroid precursors in the bone marrow. For refractory PRCA patients, the low response rate and high toxicity of alternative therapies pose a great challenge. T-cell large granular lymphocyte (T-LGL) leukemia is one of the most common conditions in secondary PRCA and also the most difficult form to manage with an inferior treatment response to other secondary PRCA forms. T-LGL leukemia exhibits sustained activation of the intracellular JAK-STAT signaling pathway. We herein report a case of PRCA associated with T-LGL leukemia that had been refractory to multiple lines of therapies and was successfully treated by ruxolitinib. The patient achieved complete remission and tolerated ruxolitinib well without occurrence of neutropenia or thrombocytopenia. This preliminary finding favors ruxolitinib as a potential salvage therapy for refractory PRCA associated with T-LGL leukemia.
Assuntos
Leucemia Linfocítica Granular Grande , Nitrilas , Pirazóis , Pirimidinas , Aplasia Pura de Série Vermelha , Humanos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Leucemia Linfocítica Granular Grande/complicações , Masculino , Pessoa de Meia-Idade , Idoso , Indução de Remissão , Terapia de SalvaçãoRESUMO
Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Hemólise/efeitos dos fármacos , Complemento C5/antagonistas & inibidores , IdosoRESUMO
A retrospective analysis was conducted based on the clinical data from 60 patients older than 16 years from January 2016 to January 2021. All the patients were newly diagnosed with severe aplastic anemia (SAA) with an absolute neutrophil count (ANC) of zero. We compared the hematological response and survival of haploidentical-allogeneic hematopoietic stem cell transplantation (HID-HSCT) (n = 25) and intensive immunosuppressive therapy (IST) (n = 35) treatments. At six months, the overall response rate and complete response were significantly higher in the HID-HSCT group than those in the IST group (84.0% vs. 40.0%, P = 0.001; 80.0% vs. 17.1%, P = 0.001). With a median follow-up of 18.5 months (4.3~30.8 months), patients in the HID-HSCT group had longer overall survival and event-free survival (80.0% vs. 47.9%, P = 0.0419; 79.2% vs. 33.5%, P = 0.0048). These data suggested that HID-HSCT might be an effective alternative treatment option for adult patients with SAA with an ANC of zero, which requires further validation in an additional prospective study.
Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Estudos Retrospectivos , Neutrófilos , Estudos Prospectivos , Doença Enxerto-Hospedeiro/etiologia , Terapia de Imunossupressão , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-TransplanteRESUMO
Although ruxolitinib improves splenomegaly and constitutional symptoms in patients with myelofibrosis (MF), a substantial proportion of patients discontinue ruxolitinib because of intolerance. This phase 2 trial investigated the safety and efficacy of jaktinib, a novel JAK inhibitor in patients with ruxolitinib-intolerant MF. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profiles. Between December 18, 2019, and November 24, 2021, 51 patients were enrolled, 45 treated with jaktinib 100 mg bid (100 mg bid group) and six received non-100 mg bid doses (non-100 mg bid group). The SVR35 at week 24 in the 100 mg bid group was 43.2% (19/44, 95% CI 29.7%-57.8%). There were 41.9% (13/31) of transfusion-independent patients with hemoglobin (HGB) ≤100 g/L who had HGB elevation ≥20 g/L within 24 weeks. The proportion of patients with a ≥50% decrease in the total symptom score (TSS 50) at week 24 was 61.8% (21/34). The most commonly reported grade ≥3 treatment-emergent adverse events (TEAEs) in the 100 mg bid group were anemia 31.1%, thrombocytopenia 22.2%, and infectious pneumonia 17.8%. A total of 16 (35.6%) in the 100 mg bid group had serious adverse events, and 4 (8.9%) were considered possibly drug related. These results indicate jaktinib can provide a treatment option for patients with MF who are intolerant to ruxolitinib.
Assuntos
Inibidores de Janus Quinases , Mielofibrose Primária , Humanos , Inibidores de Janus Quinases/efeitos adversos , Mielofibrose Primária/tratamento farmacológico , Nitrilas/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
Adult pure red cell aplasia (PRCA) is a rare syndrome characterized by a severe normocytic anemia, reticulocytopenia, and absence of erythroblasts from bone marrow. The standard treatment has not yet been established for PRCA, although cyclosporine (CsA), corticosteroids (CS) showed a response in PRCA. We retrospectively analyzed the clinical data of 60 primary and 40 secondary adult patients with acquired PRCA. The proportion of secondary PRCA is relatively high and commonly associated with large granular lymphocyte leukemia (LGLL) (28 cases, 70.0%). The remission-induced regimens included CS, CsA, or other agents, and the response rate was 66.7%, 71.4%, and 50%, respectively (P = 0.336). When treating with CsA, the response rate of LGLL-associated PRCA was lower than primary PRCA (42.1% vs 85.7%, P = 0.001). Logistic regression analysis showed that ORR was inversely related to LGLL-associated PRCA. LGLL-associated PRCA had poor therapeutic efficacy to CsA.
Assuntos
Anemia , Leucemia Linfocítica Granular Grande , Aplasia Pura de Série Vermelha , Corticosteroides/uso terapêutico , Adulto , Anemia/tratamento farmacológico , Ciclosporina/uso terapêutico , Humanos , Leucemia Linfocítica Granular Grande/diagnóstico , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Leucemia Linfocítica Granular Grande/epidemiologia , Aplasia Pura de Série Vermelha/complicações , Aplasia Pura de Série Vermelha/epidemiologia , Aplasia Pura de Série Vermelha/terapia , Estudos RetrospectivosRESUMO
Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, the effects of real-life use of low doses of EPAG combined with rabbit antithymocyte globulin (ATG)-based IST in Asian patients with SAA are yet unknown. A total of 121 previously untreated Chinese patients with SAA were enrolled in a multicenter registry of the Chinese Eastern Collaboration Group of Anemia (2014-2020): 67 patients received IST alone and 54 patients received additional EPAG. Patients receiving IST plus EPAG had a higher overall response rate (ORR) at 1 month (P = 0.002), 3 months (P = 0.028), 6 months (P = 0.006), and 12 months (P = 0.031) compared to those receiving IST alone. EPAG was the favorable factor for response efficacy at 6 months. The complete response rate in the EPAG plus IST group was 17% at 3 months, 27% at 6 months, and 32% at 12 months, compared to 7% (P = 0.069), 14% (P = 0.11), and 33% (P = 0.92) for those treated with IST alone. The 2-year overall survival rate in EPAG plus IST and IST alone groups was 98% and 88%, respectively (P = 0.078). The rate of adverse events, including clonal evolution, infection, and transaminitis, was similar in the two cohorts. The addition of EPAG to IST was well-tolerated and associated with high rates of hematologic responses among the previously untreated Chinese patients with SAA.
Assuntos
Anemia Aplástica , Anemia Aplástica/terapia , Soro Antilinfocitário/uso terapêutico , Benzoatos , China/epidemiologia , Ciclosporina/uso terapêutico , Humanos , Hidrazinas , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Pirazóis , Receptores de Trombopoetina , Resultado do TratamentoRESUMO
Hetrombopag is the only CFDA-approved thrombopoietin (TPO) receptor agonist for severe aplastic anemia (SAA) in China. Its chemical structure has an iron chelation domain. To explore the iron chelation effect of hetrombopag, we performed a post hoc analysis of the phase II clinical trial (NCT03557099). Thirty-five immunosuppressive therapy (IST)-refractory SAA patients were enrolled in the study, and the longitudinal changes of serum ferritin (SF) were assessed. At 18 weeks post-hetrombopag initiation, 51.4% of patients showed decreased SF levels by a median of 49.0 (18.1-95.5) % from baseline (median ΔSF decrease value, 917.2 ng/ml, range from 104.0 to 7030.0 ng/ml). A decrease in SF was found in 75.0% of hematologic responders and 31.6% of non-responders. Among the 24 patients with iron overload, 12 had decreased SF levels by up to 51% of the baseline. Patients with normal SF levels also showed decreased SF levels, and iron deficiency occurred in two patients. In conclusion, hetrombopag showed a powerful and rapid iron chelation effect.
Assuntos
Anemia Aplástica , Pirazolonas , Humanos , Anemia Aplástica/tratamento farmacológico , Pirazolonas/uso terapêutico , Hidrazonas/uso terapêutico , Trombopoetina/uso terapêutico , Quelantes de Ferro/uso terapêuticoRESUMO
The present study is designed to investigate the expressions of microRNA-143-3p (miR-143-3p) and Lysine acetyltransferase 6A (KAT6A) in acute myeloid leukemia (AML) samples and AML cell lines and to explore the possible effects and underlying mechanisms of miR-143-3p on the proliferation of AML cells. The expressions of miR-143-3p and KAT6A in AML samples and cell lines were detected by RT-qPCR assay. CCK-8 and flow cytometry were performed to evaluate the role of KAT6A in viability of AML cells. EdU assay was performed to determine the effects of KAT6A on proliferation of AML cells. Western blot analysis was utilized to assess the impacts of KAT6A on proliferation-related protein expressions of AML cells. ELISA assay was adopted to illustrate the influence of KAT6A on inflammatory responses of AML cells. In addition, the relationship between KAT6A and miR-143-3p was predicted by ENCORI and miRWalk, and confirmed by dual-luciferase reporter assay. Moreover, the effects of KAT6A on the proliferation of AML cells mediated with miR-143-3p were carried out by rescue experiment. The expression of KAT6A was significantly upregulated, while miR-134-4p was downregulated both in the AML tissues and in AML cell lines. In addition, the silence of KAT6A significantly inhibited the viability of AML cells. Besides, KAT6A silencing notably suppressed the proliferation of AML cells and reduced the protein expressions of Ki-67 and PCNA. Knockdown of KAT6A notably decreased the expression levels of IL-1ß, TNF-α and IL-6, and increased the expression levels of TGF-ß and IL-10. Moreover, overexpression of miR-143-3p repressed viability and proliferation of AML cells and overexpression of KAT6A partially reversed the inhibitory effects of miR-143-3p mimic on viability and proliferation of AML cells. miR-143-3p/KAT6A played an essential role in the viability and proliferation of AML cells.
Assuntos
Histona Acetiltransferases/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , MicroRNAs/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Interleucinas/metabolismo , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Regulação para CimaRESUMO
BACKGROUND: The intensive application of inorganic nitrogen has contributed to increasing the crop yield with the risk of environmental damage. High nitrogen fertilizer requirements are a long-standing problem in japonica cultivation. MATERIALS AND METHODS: In the present study, 200 recombinant inbred lines derived from two representative japonica varieties of Japanese and Chinese varieties, Akitakomachi and Liaogeng5, respectively, were planted under different nitrogen fertilization conditions. The relationships among nitrogen fertilization, genetic background, and important agronomic traits were surveyed through the phenotypic investigation and next-generation sequencing. RESULTS: The results showed that the yield components of Akitakomachi dramatically decreased along with the nitrogen reduction, whereas those of Liaogeng5 exhibited a slight decrease. The appearance quality and milling quality of both Akitakomachi and Liaogeng5 were improved, especially Liaogeng5. The recombinant inbred lines (RILs) showed similar trends to their parental lines. The QTLs analysis of important agronomic traits detected 17 loci, one QTL clustering located on chromosome 9 that corresponded to the plant height, panicle angle, grain number per panicle, harvest index, and taste value was identified to be synonymous with a previously reported gene, DEP1. The function of DEP1 was verified by a knock-out mutant constructed by CRISPR/Cas9. The dep1 mutant exhibited improved grain quality without severe yield penalty under nitrogen reduction conditions. CONCLUSION: The results of the present study provide useful information for the improvement of food security by enhancing nitrogen use efficiency.
Assuntos
Nitrogênio , Oryza , Mapeamento Cromossômico , Grão Comestível/genética , Fertilização , Oryza/genética , Locos de Características Quantitativas/genéticaRESUMO
Coronavirus disease 2019 (COVID-19) is a new human infectious disease. The etiology for this outbreak is a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus far, related research on COVID-19 is still in preliminary stage. This paper summarized the latest outcomes of corresponding study from Chinese centers and clarified the hematopoietic abnormality caused by SARS-CoV-2 and potential mechanism. Lymphopenia was common in the early stage after the onset of COVID-19. A significant decrease was observed in peripheral CD4+ and CD8+ T lymphocytes. As the illness progressed, neutrophilia emerged in several cases, and patients with severe critical pulmonary conditions showed higher neutrophils than common type. Thrombocytopenia was resulting from the consumption and/or the reduced production of platelets in damaged lungs. Anemia was not observed notably, but the decrease in hemoglobin was frequent. The activation of monocyte-macrophage system aggravates the immune damage of lung and other tissues, which leads to the increase of D-dimer, prothrombin time, and platelet consumption.
Assuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Progressão da Doença , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos , COVID-19 , China , Infecções por Coronavirus/patologia , Feminino , Hemoglobinas/análise , Humanos , Contagem de Leucócitos , Pulmão/imunologia , Pulmão/patologia , Linfopenia/virologia , Masculino , Neutrófilos , Pandemias , Pneumonia Viral/patologia , SARS-CoV-2 , Trombocitopenia/virologiaRESUMO
This current study retrospectively analyzed the clinical characteristics of 69 adult patients with acquired pure red cell aplasia (PRCA) including 40 elderly and 29 non-elderly patients from September 2009 to June 2019. The remission induction therapy regimens included cyclosporine A (CsA), corticosteroids (CS), or other immunosuppressive agents. The overall response rate was 55% (22/40) in the elderly group compared with 75.9% (22/29) in non-elderly patients (P = 0.075). In elderly patients, the best remission was achieved in the group treated with CsA than those treated with CS or other immunosuppressive agents (83.3% vs 26.7% vs 42.9%%, P = 0.004). However, outcomes of remission were similar among different treatment groups (P = 0.458) in non-elderly patients. CS induced a higher response rate in the non-elderly than that in the elderly (88.9% vs 26.7%, P = 0.009). By univariate and multivariate analysis, the clinical efficacy of elderly patients with acquired PRCA was closely associated with an induction regimen of CsA (P = 0.009; P = 0.017). In conclusion, CsA might produce higher response rate than CS and other drugs in elderly patients with acquired PRCA.
Assuntos
Ciclosporina/administração & dosagem , Terapia de Imunossupressão , Aplasia Pura de Série Vermelha/tratamento farmacológico , Indução de Remissão , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aplasia Pura de Série Vermelha/imunologia , Aplasia Pura de Série Vermelha/patologiaRESUMO
EEXPAND (phase Ib, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet counts of 50-99×109/L. The study consisted of dose-escalation and safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99×109/L) or stratum 2 (50-74×109/L), with the primary objective of determining the maximum safe starting dose (MSSD); key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, n=44; stratum 2, n=25), 24.6% (17 out of 69) of patients were still receiving treatment. The MSSD was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia [grade 4 (stratum 1, n=1; stratum 2, n=2)] was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the MSSD cohort (stratum 1, n=20; stratum 2, n=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjustment/interruption in 45.0% and 66.7% of patients in stratum 1 and stratum 2, respectively. Three cases of on-treatment deaths were reported at the MSSD. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the MSSD of 10 mg twice daily. (Registered at: clinicaltrials.gov identifier: 01317875).
Assuntos
Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Nitrilas , Mielofibrose Primária/patologia , Prognóstico , Pirimidinas , Adulto JovemRESUMO
BACKGROUND/AIMS: Cytokines IL-2 and IL-8 both participate in immune regulation. However, the relationship between polymorphisms in these two cytokines and the risk of acquired aplastic anemia (acquired AA) has not been explored. METHODS: We selected five SNPs including rs11575812, rs2069772 and rs2069762 of IL-2, rs2227306 and rs2227543 of IL-8. SNaPshot genotyping was used to test the genotypes of IL-2 and IL-8 polymorphisms in a population of 101 acquired AA patients and 165 healthy controls. RESULTS: The rs2069762 G allele appeared to be a protective mutation, but no significant differences were found in other four SNPs. We also found that rs2069762 had an impact on the transcriptional regulation. CONCLUSIONS: It could be assumed that the rs2069762 polymorphism might reduce the risk of acquired aplastic anemia, while the remaining four SNPs might not contribute to susceptibility to acquired AA in a Chinese population.
Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Interleucina-2/genética , Interleucina-8/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Anemia Aplástica/etnologia , Anemia Aplástica/patologia , Povo Asiático , Estudos de Casos e Controles , Criança , Pré-Escolar , Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Interleucina-2/imunologia , Interleucina-8/imunologia , Pessoa de Meia-Idade , RiscoRESUMO
Acquired aplastic anemia (AA) is a hematological disease characterized by failure of bone marrow hematopoiesis resulting in pancytopenia. While immune-mediated destruction of hematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired AA, the transforming growth factor-ß1 (TGF-ß1) is crucial in adjusting the immune system. The aim of our study was to investigate the role of TGF-ß1 gene polymorphisms rs1800469 and rs2317130 in susceptibility to acquired AA. Via the approach of SNaPshot, we genotyped rs1800469 and rs2317130 in 101 patients with acquired AA and 165 controls. It derived us to the conclusion that the genotype TT of rs1800469 (C/T) was significantly associated with decreased risk of acquired AA (adjusted OR = 0.39, 95% CI = 0.18-0.83, P = 0.014). Furthermore, this decreased risk was more pronounced among male patients (adjusted OR = 0.35, 95% CI = 0.13-0.95, P = 0.038) and SAA/vSAA (severe AA/very severe AA) patients (adjusted OR = 0.31, 95% CI = 0.12-0.77, P = 0.02) compared with controls in subgroup analysis. However, a significant increased risk was observed in the genotype distributions of rs2317130 for TT genotype (adjusted OR = 2.52, 95% CI = 1.03-6.19, P = 0.04) compared with the CC genotype among the SAA/vSAA patients and controls in the severity stratification analysis. Our results indicated that TGF-ß1 gene polymorphisms might be involved in the munity of acquired AA in a Chinese population. This initial analysis provides valuable clues for further study of TGF-ß1 pathway genes in acquired AA.
Assuntos
Anemia Aplástica/genética , Povo Asiático/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Fator de Crescimento Transformador beta1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/diagnóstico , Anemia Aplástica/epidemiologia , Criança , Pré-Escolar , China/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Vigilância da População , Fatores de Risco , Adulto JovemRESUMO
The inappropriate activation of complement may contribute to various immune diseases. The alternative pathway (AP) predominates during complement activation regardless of the initiating pathways. Hence, the main AP regulator factor H (FH) holds great potential as an attractive therapeutic intervention. In addition, complement receptor of the immunoglobulin superfamily (CRIg) has been demonstrated to inhibit AP and, more notably, still specifically binds to C3b/iC3b. We thus developed novel CRIg-targeted complement inhibitors by connecting the functional domains of CRIg and FH, which we termed CRIg-FH and CRIg-L-FH. CRIg-L-FH, slightly more potent than CRIg-FH, considerably inhibited both AP- and also classical pathway (CP)-mediated hemolysis and successfully eliminated the deposition of C3b/iC3b. Kinetic analysis further revealed that the binding affinity constant (KD) of CRIg/FH was in the micromolar range, consistent with its long-lasting binding to complement-attacked cells. CRIg-L-FH efficiently protected aberrant erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH) from AP- and CP-mediated complement damage (IC50 was 22.43 and 64.69 nM, respectively). Moreover, CRIg-L-FH was found to inhibit complement activation induced by the anti-Thy1 antibody in a mesangioproliferative glomerulonephritis (MPGN) rat model. Hence, CRIg-L-FH protects glomerular mesangial cells (GMCs) from complement-mediated injury and proliferative lesions. These findings strongly suggest that CRIg/FH is a potential therapeutic drug candidate for a range of complement-mediated diseases.
Assuntos
Inativadores do Complemento/metabolismo , Via Alternativa do Complemento/fisiologia , Receptores de Complemento/metabolismo , Animais , Complemento C3b/metabolismo , Fator H do Complemento/metabolismo , Modelos Animais de Doenças , Eritrócitos/metabolismo , Glomerulonefrite/metabolismo , Hemólise/fisiologia , Camundongos , Ratos , Ratos Sprague-DawleyRESUMO
Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.
Assuntos
Anemia Aplástica , Benzoatos , Pirazóis , Humanos , Masculino , Feminino , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/terapia , Adulto , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Adulto Jovem , Adolescente , Pirazolonas/uso terapêutico , Hidrazonas/uso terapêutico , Receptores de Trombopoetina/agonistas , Resultado do Tratamento , Estudos Prospectivos , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Idoso , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Tiazóis , TiofenosRESUMO
Aplastic anemia (AA) is a bone marrow failure disease caused by abnormal activation of T lymphocytes, resulting in the apoptosis of hematopoietic cells and bone marrow failure. Currently, hematopoietic stem cell transplantation (HSCT), immunosuppressive - therapy (IST), and supportive care (e.g. transfusion adjuvant therapy, hematopoietic growth factors, and prevention of infection) are the main treatments of AA. Granulocyte transfusion has recently been accepted as an useful adjuvant therapy of HSCT and intensive IST. This article reported a severe AA patient who failed to respond to IST, but achieved spontaneous remission three times after granulocyte transfusions from related donors. Such cases have rarely been reported. Existence of human leukocyte antigen (HLA) cross between the patient and his relatives may influence the T cell-mediated immunity, which might explain this patient's recovery.