RESUMO
DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P < 0.05). Notably, elevated DARS expression was linked to splenomegaly in MPNs patients. The expression of DARS showed a negative correlation with CD4+ T cells (R = - 0.451, P = 0.0004) and CD4+ T/CD8+ T cell ratio (R = - 0.3758, P = 0.0040), as well as with CD68+ tumor-associated macrophages (R = 0.4037, P = 0.0017). Conversely, it was positively correlated with IL-2 (R = 0.5419, P < 0.001), IL-5 (R = 0.3161, P = 0.0166), IL-6 (R = 0.2992, P = 0.0238), and IFN-γ (R = 0.3873, P = 0.0029). These findings underscore a significant association between DARS expression in MPNs patients and specific clinical characteristics, as well as immune cell composition. Further investigation into the interplay between DARS and the immune microenvironment in MPNs could shed light on the underlying mechanisms of MPNs pathogenesis and immune dysregulation.
Assuntos
Proteínas de Fusão bcr-abl , Transtornos Mieloproliferativos , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Idoso , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismoRESUMO
Typical BCR::ABL1-negative myeloproliferative neoplasms (MPN) are mainly referred to as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofbrosis (PMF). Granulocytes in MPN patients are involved in their inflammation and form an important part of the pathophysiology of MPN patients. It has been shown that the immunophenotype of granulocytes in MPN patients is altered. We used flow cytometry to explore the immunophenotype of MPN patients and correlate it with clinical parameters. The results showed that PMF patients and PV patients had higher CD15+CD11b+ granulocytes than ET patients and normal controls. When grouped by gene mutation, changes in the granulocyte immunophenotype of MPN patients were independent of the JAK2V617F and CALR mutations. There was no significant heterogeneity in immunophenotype between ET patients and Pre-PMF, and between Overt-PMF and Pre-PMF patients. Granulocytes from some MPN patients showed an abnormal CD13/CD16 phenotype with a significant increase in mature granulocytes on molecular and cytomorphological grounds, and this abnormal pattern occurred significantly more frequently in PMF patients than in ET patients. CD15-CD11b- was negatively correlated with WBC and Hb and positively correlated with DIPSS score, whereas high CD10+ granulocytes were significantly and negatively associated with prognostic system IPSS and DIPSS scores in PMF patients. In conclusion, this study demonstrates the landscape of bone marrow granulocyte immunophenotypes in MPN patients. MPN patients, especially those with PMF, have a significant granulocyte developmental overmaturation phenotype. CD10+ granulocytes may be involved in the prognosis of PMF patients.
Assuntos
Citometria de Fluxo , Proteínas de Fusão bcr-abl , Granulócitos , Imunofenotipagem , Transtornos Mieloproliferativos , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Granulócitos/patologia , Adulto , Idoso , Proteínas de Fusão bcr-abl/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/patologia , Janus Quinase 2/genética , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Idoso de 80 Anos ou mais , China , Adulto Jovem , Calreticulina/genética , Antígeno CD11b/genética , Policitemia Vera/genética , Policitemia Vera/patologia , Policitemia Vera/imunologia , Mutação , Povo Asiático/genética , População do Leste AsiáticoRESUMO
Classic myeloproliferative neoplasms lacking the Philadelphia chromosome are stem cell disorders characterized by the proliferation of myeloid cells in the bone marrow and increased counts of peripheral blood cells. The occurrence of thrombotic events is a common complication in myeloproliferative neoplasms. The heightened levels of cytokines play a substantial role in the morbidity and mortality of these patients, establishing a persistent proinflammatory condition that culminates in thrombosis. The etiology of thrombosis remains intricate and multifaceted, involving blood cells and endothelial dysfunction, the inflammatory state, and the coagulation cascade, leading to hypercoagulability. Leukocytes play a pivotal role in the thromboinflammatory process of myeloproliferative neoplasms by releasing various proinflammatory and prothrombotic factors as well as interacting with other cells, which contributes to the amplification of the clotting cascade and subsequent thrombosis. The correlation between increased leukocyte counts and thrombotic risk has been established. However, there is a need for an accurate biomarker to assess leukocyte activation. Lastly, tailored treatments to address the thrombotic risk in myeloproliferative neoplasms are needed. Therefore, this review aims to summarize the potential mechanisms of leukocyte involvement in myeloproliferative neoplasm thromboinflammation, propose potential biomarkers for leukocyte activation, and discuss promising treatment options for controlling myeloproliferative neoplasm thromboinflammation.
Assuntos
Inflamação , Leucócitos , Transtornos Mieloproliferativos , Trombose , Humanos , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/patologia , Trombose/etiologia , Trombose/patologia , Trombose/imunologia , Leucócitos/imunologia , Leucócitos/patologia , Leucócitos/metabolismo , Inflamação/patologia , AnimaisRESUMO
Neutrophils are an essential component of the innate immune response, but their prolonged activation can lead to chronic inflammation. Consequently, neutrophil homeostasis is tightly regulated through balance between granulopoiesis and clearance of dying cells. The bone marrow is both a site of neutrophil production and the place they return to and die. Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by the mutations in three types of molecular markers, with emphasis on Janus kinase 2 gene mutation (JAK2V617F). The MPN bone marrow stem cell niche is a site of chronic inflammation, with commonly increased cells of myeloid lineage, including neutrophils. The MPN neutrophils are characterized by the upregulation of JAK target genes. Additionally, MPN neutrophils display malignant nature, they are in a state of activation, and with deregulated apoptotic machinery. In other words, neutrophils deserve to be placed in the midst of major events in MPN. Our crucial interest in this review is better understanding of how neutrophils die in MPN mirrored by defects in apoptosis and to what possible extent they can contribute to MPN pathophysiology. We tend to expect that reduced neutrophil apoptosis will establish a pathogenic link to chronic inflammation in MPN.
Assuntos
Neoplasias Hematológicas/imunologia , Imunidade Inata , Transtornos Mieloproliferativos/imunologia , Neutrófilos/imunologia , Substituição de Aminoácidos , Animais , Doença Crônica , Neoplasias Hematológicas/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos/genéticaRESUMO
Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11E76K) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11E76K/+ BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11E76K/+ MPN cells produced excessive IL-1ß, but not IL-6, T NF-α, IFN-γ, IL-1α, or other inflammatory cytokines. Depletion of the IL-1ß receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/+/IL-1R-/- double mutant mice. These findings suggest IL-1ß signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.
Assuntos
Células-Tronco Hematopoéticas , Inflamação , Interleucina-1beta , Leucemia Mielomonocítica Juvenil , Animais , Medula Óssea/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/metabolismo , Leucemia Mielomonocítica Juvenil/imunologia , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/patologia , Camundongos , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Receptores de Interleucina-1/deficiência , Microambiente TumoralRESUMO
Breakpoint cluster region-Abelson (BCR-ABL) negative myeloproliferative neoplasms (MPNs) are chronic myeloid neoplasms initiated by the acquisition of gene mutation(s) in a haematopoietic stem cell, leading to clonal expansion and over-production of blood cells and their progenitors. MPNs encompass a spectrum of disorders with overlapping but distinct molecular, laboratory and clinical features. This includes polycythaemia vera, essential thrombocythaemia and myelofibrosis. Dysregulation of the immune system is key to the pathology of MPNs, supporting clonal evolution, mediating symptoms and resulting in varying degrees of immunocompromise. Targeting immune dysfunction is an important treatment strategy. In the present review, we focus on the immune landscape in patients with MPNs - the role of inflammation in disease pathogenesis, susceptibility to infection and emerging strategies for therapeutic immune modulation. Further detailed work is required to delineate immune perturbation more precisely in MPNs to determine how and why vulnerability to infection differs between clinical subtypes and to better understand how inflammation results in a competitive advantage for the MPN clone. These studies may help shed light on new designs for disease-modifying therapies.
Assuntos
Imunoterapia , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/terapia , Animais , Proteínas de Fusão bcr-abl/análise , Humanos , Imunidade , Imunoterapia/métodos , Infecções/imunologia , Infecções/patologia , Infecções/terapia , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Transtornos Mieloproliferativos/patologia , Evasão TumoralAssuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Idoso , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Estudos de Coortes , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Imunogenicidade da Vacina , Imunoglobulina G/biossíntese , Cinética , Leucemia/imunologia , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Transtornos Mieloproliferativos/imunologia , Fatores de Tempo , VacinaçãoRESUMO
BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors-related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors' effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.
Assuntos
Anti-Inflamatórios/uso terapêutico , Imunossupressores/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Animais , Anti-Inflamatórios/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/efeitos adversos , Infecções/etiologia , Inibidores de Janus Quinases/efeitos adversos , Transtornos Mieloproliferativos/imunologiaAssuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/imunologia , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/genética , COVID-19/prevenção & controle , COVID-19/virologia , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificaçãoAssuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Transtornos Mieloproliferativos/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Humanos , Transtornos Mieloproliferativos/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas de mRNARESUMO
The immune microenvironment is a critical driver and regulator of leukemic progression and hematological disease. Recent investigations have demonstrated that multiple immune components play a central role in regulating hematopoiesis, and dysfunction at the immune cell level significantly contributes to neoplastic disease. Immune cells are acutely sensitive to remodeling by leukemic inflammatory cytokine exposure. Importantly, immune cells are the principal cytokine producers in the hematopoietic system, representing an untapped frontier for clinical interventions. Due to a proinflammatory cytokine environment, dysregulation of immune cell states is a hallmark of hematological disease and neoplasia. Malignant immune adaptations have profound effects on leukemic blast proliferation, disease propagation, and drug-resistance. Conversely, targeting the immune landscape to restore hematopoietic function and limit leukemic expansion may have significant therapeutic value. Despite the fundamental role of the immune microenvironment during the initiation, progression, and treatment response of hematological disease, a detailed examination of how leukemic cytokines alter immune cells to permit, promote, or inhibit leukemia growth is lacking. Here we outline an immune-based model of leukemic transformation and highlight how the profound effect of immune alterations on the trajectory of malignancy. The focus of this review is to summarize current knowledge about the impacts of pro- and anti-inflammatory cytokines on immune cells subsets, their modes of action, and immunotherapeutic approaches with the potential to improve clinical outcomes for patients suffering from hematological myeloid malignancies.
Assuntos
Citocinas/imunologia , Neoplasias Hematológicas/imunologia , Transtornos Mieloproliferativos/imunologia , Animais , Humanos , Imunidade Inata , Transdução de SinaisRESUMO
Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in "education" and "crafting" of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers.
Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/metabolismo , Transtornos Mieloproliferativos/metabolismo , Microambiente Tumoral , Animais , Biomarcadores Tumorais/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/patologia , Policitemia Vera/genética , Policitemia Vera/imunologia , Policitemia Vera/metabolismo , Policitemia Vera/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/imunologia , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Transdução de Sinais , Trombocitemia Essencial/genética , Trombocitemia Essencial/imunologia , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/patologia , Microambiente Tumoral/imunologiaRESUMO
Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.
Assuntos
Neoplasias Hematológicas/imunologia , Transtornos Mieloproliferativos/imunologia , Proteínas de Neoplasias/imunologia , Neutrófilos/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Proteínas de Neoplasias/genética , Neutrófilos/patologia , Cromossomo FiladélfiaAssuntos
Vacinas contra COVID-19/administração & dosagem , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/imunologia , Pirazóis/uso terapêutico , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Nitrilas , Pirimidinas , SARS-CoV-2/imunologiaRESUMO
OBJECTIVE: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). METHODS: 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. RESULTS: In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. CONCLUSIONS: Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Transtornos Mieloproliferativos/terapia , Plasmaferese/métodos , Aplasia Pura de Série Vermelha/prevenção & controle , Reação Transfusional/prevenção & controle , Sistema ABO de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/mortalidade , Incompatibilidade de Grupos Sanguíneos/terapia , Transfusão de Eritrócitos/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia/imunologia , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/mortalidade , Aplasia Pura de Série Vermelha/etiologia , Aplasia Pura de Série Vermelha/imunologia , Aplasia Pura de Série Vermelha/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Doadores de Tecidos , Reação Transfusional/etiologia , Reação Transfusional/imunologia , Reação Transfusional/mortalidade , Transplante Homólogo , Resultado do TratamentoAssuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Transtornos Mieloproliferativos/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , COVID-19/complicações , Vacinas contra COVID-19/administração & dosagem , Humanos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas de mRNARESUMO
BACKGROUND: Safety and immunogenicity of BNT162b2 mRNA vaccine are unknown in hematological patients; both were evaluated prospectively in 42 patients with multiple myeloma (MM) and 50 with myeloproliferative malignancies (MPM) (20 chronic myeloid leukemias and 30 myeloproliferative neoplasms), all of them on active anti-cancer treatment, in comparison with 36 elderly controls not suffering from cancer. Subjects serologically and/or molecularly (by nasal/throat swab) positives at basal for SARS-CoV-2 were excluded. Primary endpoint was to compare titers of neutralizing anti-SARS-CoV-2 IgG and seroprotection rates among the cohorts at 3 and 5 weeks from first dose. METHODS: Titration was done using LIAISON® SARS-CoV-2 S1/S2 IgG test, a quantitative chemiluminescent immunoassay approved by FDA on the basis of robust evidences of concordance (94.4%) between the test at cutoff of 15 AU/mL and the Plaque Reduction Neutralization Test 90% at 1:40 ratio. Cutoff of 15 AU/mL was assumed to discriminate responders to vaccination with a protective titer. Cohorts were compared using Fisher' exact test and the Mann-Whitney test as appropriated. Geometric mean concentrations (GMCs), geometric mean ratios and response rates after 1st and 2nd dose were compared in each cohort by Wilcoxon and McNemar tests, respectively. RESULTS: At 5 weeks, GMC of IgG in elderly controls was 353.3 AU/mL versus 106.7 in MM (p = 0.003) and 172.9 in MPM patients (p = 0.049). Seroprotection rate at cutoff of 15 AU/mL was 100% in controls compared to 78.6% in MM (p = 0.003) and 88% in MPM patients (p = 0.038). In terms of logarithm of IgG titer, in a generalized multivariate linear model, no gender effect was observed (p = 0.913), while there was a significant trend toward lower titers by increasing age (p < 0.001) and in disease cohorts with respect to controls (MM: p < 0.001 and MPM: p < 0.001). An ongoing treatment without daratumumab was associated with higher likelihood of response in MM patients (p = 0.003). No swabs resulted positive on each time point. No safety concerns were observed. CONCLUSIONS: BNT162b2 has demonstrated to be immunogenic at different extent among the cohorts. Response was 88% and robust in MPM patients. MM patients responded significantly less, particularly those on anti-CD38-based treatment. These latter patients should be advised to maintain masks and social distancing regardless of vaccination status, and their cohabiting family members need to be vaccinated in order to reduce the risk of contagion from the family. Additional boosters and titer monitoring could be considered. Trial registration Study was formally approved by the IRCCS Central Ethical Committee of Regione Lazio in January 2021 (Prot. N-1463/21).
Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Mieloma Múltiplo/complicações , Transtornos Mieloproliferativos/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacina BNT162 , COVID-19/imunologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Imunogenicidade da Vacina , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Transtornos Mieloproliferativos/imunologia , Dados Preliminares , Estudos Prospectivos , SARS-CoV-2/imunologiaRESUMO
The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.
Assuntos
Células-Tronco Hematopoéticas/imunologia , Imunoterapia/métodos , Inflamação/imunologia , Transtornos Mieloproliferativos/terapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Calreticulina/genética , Calreticulina/imunologia , Calreticulina/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Inflamação/genética , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Janus Quinase 2/metabolismo , Mutação/imunologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Cromossomo Filadélfia , Linfócitos T/metabolismo , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: During eosinophil differentiation, the granule eosinophil major basic protein 1 (eMBP1) is synthesized as a 32-kDa precursor form, referred to as proMBP1, which is processed into the 14-kDa mature form of eMBP1. The prevalence of these two forms of MBP1 in most pathological conditions remains unknown. OBJECTIVE: To develop the immunoassays that differentiate mature eMBP1 and proMBP1 and apply them to analyze their levels in biological fluids from patients with eosinophilia and hematologic disorders. METHODS: We produced a series of monoclonal antibodies and selected pairs capable of discriminating between the two molecular forms of eMBP1. Radioimmunoassay (RIA) was performed to simultaneously quantitate the levels of mature eMBP1 and proMBP1 in secretions from patients with chronic rhinosinusitis (CRS) and sera from patients with hypereosinophilic syndrome (HES) and other myeloproliferative disorders. RESULTS: The novel immunoassays possessed less than 1% crossreactivity between mature eMBP1 and proMBP1. Mature eMBP1, but not proMBP1, was found in nasal secretions of CRS patients. In contrast, elevated serum levels of mature eMBP1 and proMBP1 were observed in approximately 60% and 90% of HES patients, respectively, with proMBP1 present in greater quantities than mature eMBP1. Patients with several myeloproliferative disorders also showed high serum levels of proMBP1 while mature eMBP1 remained at basal levels. CONCLUSION: The novel immunoassays successfully differentiated mature eMBP1 and proMBP1 in human biological fluids. Further studies addressing the clinical correlates of these assays will help to develop biomarkers to diagnose and monitor patients with eosinophilia and myeloproliferative disorders.
Assuntos
Proteína Básica Maior de Eosinófilos/sangue , Eosinofilia/diagnóstico , Imunoensaio/métodos , Transtornos Mieloproliferativos/diagnóstico , Proteoglicanas/sangue , Anticorpos Monoclonais/imunologia , Proteína Básica Maior de Eosinófilos/imunologia , Eosinofilia/imunologia , Humanos , Transtornos Mieloproliferativos/imunologia , Proteoglicanas/imunologiaRESUMO
Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.