RESUMO
Sepsis survivors exhibit immune dysfunction, hematological changes, and increased risk of infection. The long-term impacts of sepsis on hematopoiesis were analyzed using a surgical model of murine sepsis, resulting in 50% survival. During acute disease, phenotypic hematopoietic stem and progenitor cells (HSPCs) were reduced in the bone marrow (BM), concomitant with increased myeloid colony-forming units and extramedullary hematopoiesis. Upon recovery, BM HSPCs were increased and exhibited normal function in the context of transplantation. To evaluate hematopoietic responses in sepsis survivors, we treated recovered sham and cecal ligation and puncture mice with a mobilizing regimen of granulocyte colony-stimulating factor (G-CSF) at day 20 post-surgery. Sepsis survivors failed to undergo emergency myelopoiesis and HSPC mobilization in response to G-CSF administration. G-CSF is produced in response to acute infection and injury to expedite the production of innate immune cells; therefore, our findings contribute to a new understanding of how sepsis predisposes to subsequent infection.
Assuntos
Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Mielopoese , Sepse , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Camundongos Endogâmicos C57BL , Mielopoese/efeitos dos fármacos , Sepse/complicações , SobreviventesRESUMO
We evaluated whether viable and non-viable Lacticaseibacillus rhamnosus CRL1505 (Lr05V or Lr05NV, respectively) was able to improve emergency myelopoiesis induced by Streptococcus pneumoniae (Sp) infection. Adult Swiss-mice were orally treated with Lr05V or Lr05NV during five consecutive days. The Lr05V and Lr05NV groups and untreated control group received an intraperitoneal dose of cyclophosphamide (Cy-150 mg/kg). Then, the mice were nasally challenged with Sp (107 UFC/mice) on day 3 post-Cy injection. After the pneumococcal challenge, the innate and myelopoietic responses were evaluated. The control group showed a high susceptibility to pneumococcal infection, an impaired innate immune response and a decrease of hematopoietic stem cells (HSCs: Lin-Sca-1+c-Kit+), and myeloid multipotent precursors (MMPs: Gr-1+Ly6G+Ly6C-) in bone marrow (BM). However, lactobacilli treatments were able to significantly increase blood neutrophils and peroxidase-positive cells, while improving cytokine production and phagocytic activity of alveolar macrophages. This, in turn, led to an early Sp lung clearance compared to the control group. Furthermore, Lr05V was more effective than Lr05NV to increase growth factors in BM, which allowed an early HSCs and MMPs recovery with respect to the control group. Both Lr05V and Lr05NV were able to improve BM emergency myelopiesis and protection against respiratory pathogens in mice undergoing chemotherapy.
Assuntos
Hospedeiro Imunocomprometido , Lacticaseibacillus rhamnosus , Mielopoese , Probióticos , Streptococcus pneumoniae , Animais , Camundongos , Mielopoese/efeitos dos fármacos , Lacticaseibacillus rhamnosus/imunologia , Probióticos/administração & dosagem , Probióticos/farmacologia , Streptococcus pneumoniae/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Imunidade Inata , Modelos Animais de Doenças , Citocinas/metabolismo , Ciclofosfamida/farmacologia , Neutrófilos/imunologia , MasculinoRESUMO
Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Reação Leucemoide/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores , Técnicas de Cultura de Células , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Ensaios de Triagem em Larga Escala , Humanos , Imuno-Histoquímica , Reação Leucemoide/etiologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-IdadeRESUMO
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes , Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Mutação , Mielopoese/efeitos dos fármacos , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Sulfonamidas , Proteína X Associada a bcl-2 , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Infectious pneumonia is one of the most common complications after bone marrow transplantation (BMT), which is considered to be associated with poor reconstitution and functional maturation of alveolar macrophages (AMs) post-transplantation. Here, we present evidence showing that lack of IL-13-secreting group 2 innate lymphoid cells (ILC2s) in the lungs may underlay poor AM reconstitution in a mouse model of haploidentical BMT (haplo-BMT). Recombinant murine IL-13 was able to potentiate monocyte-derived AM differentiation in vitro. When intranasally administered, a cocktail of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-13, and CCL2 not only promoted donor monocyte-derived AM reconstitution in haplo-BMT-recipient mice but also enhanced the innate immunity of the recipient animals against pulmonary bacterial infection. These results provide a useful clue for a clinical strategy to prevent pulmonary bacterial infection at the early stage of recipients post-BMT.
Assuntos
Transplante de Medula Óssea , Diferenciação Celular , Citocinas/metabolismo , Reconstituição Imune , Macrófagos Alveolares/fisiologia , Mielopoese , Animais , Transplante de Medula Óssea/métodos , Diferenciação Celular/efeitos dos fármacos , Citocinas/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos Alveolares/citologia , Macrófagos Alveolares/efeitos dos fármacos , Camundongos , Modelos Animais , Mielopoese/efeitos dos fármacos , Transplante HaploidênticoRESUMO
Myelosuppression is the major dose-limiting toxicity of cancer chemotherapy. There have been many attempts to find new strategies that reduce myelosuppression. The dietary supplementation with lactic acid bacteria (LAB) improved respiratory innate immune response and the resistance against respiratory pathogens in immunosupressed hosts. Although LAB viability is an important factor in achieving optimal protective effects, non-viable LAB are capable of stimulating immunity. In this work, we studied the ability of oral preventive administration of viable and non-viable Lactobacillus rhamnosus CRL1505 or L. plantarum CRL1506 (Lr05, Lr05NV, Lp06V or Lp06NV, respectively) to minimize myelosuppressive and immunosuppressive effects derived from chemotherapy. Cyclophosphamide (Cy) impaired steady-state myelopoiesis in lactobacilli-treated and untreated control mice. Lr05V, Lr05NV and Lp06V treatments were the most effective to induce the early recovery of bone marrow (BM) tissue architecture, leukocytes, myeloid, pool mitotic and post-mitotic, peroxidase positive, and Gr-1Low/High cells in BM. We selected the CRL1505 strain for being the one capable of maintaining its myelopoiesis-enhancing properties in its non-viable form. Although the CRL1505 treatments do not modify the Cy ability to induce apoptosis, both increased the incorporation of BrdU in BM cells. Consequently, Lr05NV and Lr05V treatments were able to promote early recovery of LSK cells (Lin-Sca-1+c-Kit+ cells), multipotent progenitors (Lin-Sca-1+c-Kit+CD34+ cells), and myeloid cells (Gr-1+Ly6G+Ly6C- cells) with respect to the untreated Cy control. In addition, these treatments were able to increase the frequency of IL17A-producing innate lymphoid cells in the intestinal lamina propria (IL-17A+RORγt+CD4-NKp46+ cells) after Cy injection. These results were correlated with an increase in the IL-17A serum levels, a GM-CSF high expression and a CXCL12 lower expression in BM. Therefore, both Lr05V and Lr05NV treatments are able to activate beneficially the IL-17A/GM-CSF axis and accelerate the recovery of Cy-induced immunosuppression by increasing BM myeloid precursors. We demonstrated for the first time the beneficial effect of CRL1505 strain on myelopoiesis affected by a chemotherapeutic drug. Furthermore, Lr05NV could be a good and safe resource for reducing chemotherapy-induced leukopenia. The results are a starting point for future research and open up broad prospects for future applications of the immunobiotics.
Assuntos
Ciclofosfamida/toxicidade , Hospedeiro Imunocomprometido/efeitos dos fármacos , Lacticaseibacillus rhamnosus/imunologia , Lactobacillus/imunologia , Mielopoese/efeitos dos fármacos , Probióticos/administração & dosagem , Administração Oral , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/imunologia , Imunossupressores/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Contagem de Leucócitos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Camundongos , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Mielopoese/imunologiaRESUMO
Differentiation Syndrome (DS) has been identified in a subset of patients undergoing treatment with novel classes of differentiating therapies for acute myeloid leukemia (AML) such as IDH and FLT3 inhibitors. While DS is a well-known treatment-related complication in acute promyelocytic leukemia (APL), efforts are still ongoing to standardize diagnostic and treatment parameters for DS in AML. Though the rates of incidence vary, many of the signs and symptoms of DS are common between APL and AML. So, DS can lead to fatal complications in AML, but prompt management is usually effective and rarely necessitates interruption or discontinuation of AML therapy.
Assuntos
Antineoplásicos/efeitos adversos , Síndrome da Liberação de Citocina/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Corticosteroides/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/efeitos adversos , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Edema/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Febre/induzido quimicamente , Humanos , Hipotensão/induzido quimicamente , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/complicações , Terapia de Alvo Molecular/efeitos adversos , Proteínas de Neoplasias/antagonistas & inibidores , Derrame Pleural/induzido quimicamente , Transtornos Respiratórios/induzido quimicamente , Tretinoína/efeitos adversos , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresRESUMO
Inflammatory cytokines exert different effects on hematopoietic stem cells (HSCs), lead to the development of various cell lineages in bone marrow (BM) and are thus a differentiation axis for HSCs. The content used in this article has been obtained by searching PubMed database and Google Scholar search engine of English-language articles (1995-2020) using "Hematopoietic stem cell," "Inflammatory cytokine," "Homeostasis," and "Myelopoiesis." Inflammatory cytokines are involved in the differentiation and proliferation of hematopoietic progenitors to compensate for cellular death due to inflammation. Since each of these cytokines differentiates HSCs into a specific cell line, the difference in the effect of these cytokines on the fate of HSC progenitors can be predicted. Inhibitors of these cytokines can also control the inflammatory process as well as the cells involved in leukemic conditions. In general, inflammatory signaling can specify the dominant cell line in BM to counteract inflammation and leukemic condition via stimulating or inhibiting hematopoietic progenitors. Therefore, detection of the effects of inflammatory cytokines on the differentiation of HSCs can be an appropriate approach to check inflammatory and leukemic conditions and the suppression of these cytokines by their inhibitors allows for control of homeostasis in stressful conditions.
Assuntos
Linhagem da Célula/imunologia , Citocinas/metabolismo , Células-Tronco Hematopoéticas/imunologia , Animais , Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Mielopoese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Chronic myelomonocytic leukemia (CMML) is characterized by myelomonocytic bias and monocytic proliferation. Whether cell-intrinsic innate immune or inflammatory upregulation mediate disease pathogenesis and phenotype or whether the degree of aberrant monocytic differentiation influences outcomes remains unclear. We compared the transcriptomic features of bone marrow CD34+ cells from 19 patients with CMML and compared to healthy individuals. A total of 1495 genes had significantly differential expression in CMML (q<0.05, fold change>2), including 1271 genes that were significantly upregulated and 224 that were significantly downregulated in CMML. Top upregulated genes were associated with interferon (IFN) alpha and beta signaling, chemokine receptors, IFN gamma, G protein-coupled receptor ligand signaling, and genes involved in immunomodulatory interactions between lymphoid and non-lymphoid cells. Additionally, 6 gene sets were differentially upregulated and 139 were significantly downregulated in patients with myeloproliferative compared to myelodysplastic CMML. A total of 23 genes involved in regulation of monopoiesis were upregulated in CMML compared to healthy controls. We developed a prediction model using Cox regression including 3 of these genes, which differentiated patients into two prognostic subsets with distinct survival outcomes. This data warrants further evaluation of the roles and therapeutic potential of type I IFN signaling and monopoiesis in CMML.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon Tipo I/administração & dosagem , Leucemia Mielomonocítica Crônica , Mielopoese/efeitos dos fármacos , Proteínas de Neoplasias , Regulação para Cima/efeitos dos fármacos , Feminino , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genéticaRESUMO
TGN1412, a superagonist monoclonal antibody targeting CD28, caused cytokine storm in six healthy volunteers in a first-in-man study in 2006. Despite clinical improvement and termination of the cytokine release syndrome within days, anemia persisted in all patients with hemoglobin reaching baseline levels as much as 6 months later. Granulocytic dysplasia continued for 20 days in association with increased expression of CD69 and IL-4, but reduced IL-10; with resolution, this profile reversed to higher IL-10 expression and counter-balanced circannual cycling of IL-4 and IL-10 thereafter over 7 months. Along with immune cell subset and cytokine correlates monitored over 2 years, these observations offer unique insights into the expected changes in myelopoiesis and natural resolution in otherwise healthy young individuals in response to acute inflammation and cytokine storm in the absence of concomitant infection or comorbidity.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD28/imunologia , Síndrome da Liberação de Citocina/imunologia , Inflamação/imunologia , Leucócitos Mononucleares/imunologia , Mielopoese/imunologia , Adulto , Síndrome da Liberação de Citocina/induzido quimicamente , Citocinas/metabolismo , Humanos , Inflamação/induzido quimicamente , Masculino , Mielopoese/efeitos dos fármacos , Adulto JovemRESUMO
The ability to predict the incidence of chemotherapy-induced neutropenia in early drug development can inform risk monitoring and mitigation strategies, as well as decisions on advancing compounds to clinical trials. In this report, a physiological model of granulopoiesis that incorporates the drug's mechanism of action on cell cycle proliferation of bone marrow progenitor cells was extended to include the action of the cytotoxic agents paclitaxel, carboplatin, doxorubicin, and gemcitabine. In vitro bone marrow studies were conducted with each compound, and results were used to determine the model's drug effect parameters. Population simulations were performed to predict the absolute neutrophil count (ANC) and incidence of neutropenia for each compound, which were compared to results reported in the literature. In addition, using the single agent in vitro study results, the model was able to predict ANC time course in response to paclitaxel plus carboplatin in combination, which compared favorably to the results reported in a phase 1 clinical trial of 46 patients (r2 = 0.70). Model simulations were used to compare the relative risk (RR) of neutropenia in patients with high baseline ANCs for five chemotherapeutic regimens: doxorubicin (RR = 0.59), paclitaxel plus carboplatin combination (RR = 0.079), carboplatin (RR = 0.047), paclitaxel (RR = 0.031), and gemcitabine (RR = 0.013). Finally, the model was applied to quantify the reduced incidence of neutropenia with coadministration of pegfilgrastim or filgrastim, for both paclitaxel and the combination of paclitaxel plus carboplatin. The model provides a framework for predicting clinical neutropenia using in vitro bone marrow studies of anticancer agents that may guide drug development decisions.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Filgrastim/administração & dosagem , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neutropenia/epidemiologia , Polietilenoglicóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Medula Óssea/efeitos dos fármacos , Medula Óssea/crescimento & desenvolvimento , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Células Cultivadas , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Humanos , Incidência , Mielopoese/efeitos dos fármacos , Neoplasias/sangue , Neutropenia/induzido quimicamente , Neutropenia/diagnóstico , Neutropenia/prevenção & controle , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Cultura Primária de Células , Medição de Risco/métodos , Resultado do Tratamento , GencitabinaRESUMO
Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aromatase/metabolismo , Fatores Imunológicos/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Células HEK293 , Humanos , Células K562 , Masculino , Megacariócitos/efeitos dos fármacos , Megacariócitos/patologia , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Mielopoese/fisiologia , Especificidade por Substrato , Trombocitopenia/patologiaRESUMO
Acute exposure to high doses of radiation leads to severe myelosuppression, but few treatments are currently available to treat hematopoietic syndrome of acute radiation syndrome. Granulocyte colony stimulating factors (e.g., filgrastim) stimulate proliferation of neutrophil precursors and enhance mature neutrophil function. Owing to ethical constraints on conducting clinical research in lethally irradiated humans, we developed a model-based strategy to integrate preclinical experience in irradiated nonhuman primates (NHPs) and other clinical myelosuppressive conditions to inform filgrastim dosing to treat hematopoietic syndrome of acute radiation syndrome. Models predicting neutrophil counts and overall survival based on drug exposures were calibrated and scaled from NHPs to adult and pediatric human subjects. Several scenarios were examined investigating variations in filgrastim doses, dose frequency, treatment initiation, and duration, as well as the effect of age and radiation dose rate. Model-based simulations and established safety profiles supported that a subcutaneous filgrastim dose of 10 µg/kg once daily provides a significant survival benefit (50%) over placebo in both adults and children, provided that the treatment is initiated within 1-14 days after radiation exposure and lasts 2-3 weeks. For treatment durations of longer than 3 weeks, filgrastim treatment is not expected to provide significantly greater benefit. This survival benefit is expected to hold for the wide range of radiation doses and dose rates (0.01-1,000 Gy/hours) examined.
Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Filgrastim/administração & dosagem , Fármacos Hematológicos/administração & dosagem , Síndrome Aguda da Radiação/mortalidade , Adulto , Fatores Etários , Animais , Criança , Simulação por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Precursoras de Granulócitos/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Macaca mulatta , Masculino , Mielopoese/efeitos dos fármacos , Medição de Risco/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. RESULTS: In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine's versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. CONCLUSIONS: Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.
Assuntos
Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Neoplasias da Mama/terapia , Imunoterapia Adotiva/métodos , Células Supressoras Mieloides/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Azacitidina/uso terapêutico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Metilases de Modificação do DNA/antagonistas & inibidores , Feminino , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mielopoese/efeitos dos fármacosRESUMO
OBJECTIVE: Increased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis. METHODS: A selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)-fed wild-type (WT) or Apoe-/- mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe-/- mice were assessed. RESULTS: TG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe-/- mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe-/- mice which was substantially reduced by TG101348. CONCLUSIONS: Selective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe-/- mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis.
Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Células-Tronco Hematopoéticas/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Mielopoese/efeitos dos fármacos , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Aorta/enzimologia , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/enzimologia , Células-Tronco Hematopoéticas/patologia , Janus Quinase 2/metabolismo , Leucocitose/enzimologia , Leucocitose/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Transdução de SinaisRESUMO
We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease.
Assuntos
Extratos Celulares/farmacologia , Células Dendríticas/efeitos dos fármacos , Endorribonucleases/metabolismo , Imunidade Inata/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Células Progenitoras Mieloides/efeitos dos fármacos , Placenta/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Endorribonucleases/genética , Feminino , Redes Reguladoras de Genes , Camundongos Endogâmicos BALB C , Células Progenitoras Mieloides/imunologia , Células Progenitoras Mieloides/metabolismo , Mielopoese/efeitos dos fármacos , Placenta/imunologia , Placenta/metabolismo , Gravidez , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Transcriptoma , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/genéticaRESUMO
Tumor growth and its chemotherapeutic regimens manifest myelosuppression, which is one of the possible causes underlying the limited success of immunotherapeutic anticancer strategies. Hence, approaches are being designed to develop safer therapeutic regimens that may have minimal damaging action on the process of myelopoiesis. 3-Bromopyruvate (3-BP) is a highly potent antimetabolic agent displaying a broad spectrum antineoplastic activity. However, 3-BP has not been investigated for its effect on the process of myelopoiesis in a tumor-bearing host. Hence, in this investigation, we studied the myelopoietic effect of in vivo administration of 3-BP to a murine host bearing a progressively growing ascitic thymoma designated as Dalton's lymphoma (DL). 3-BP administration to the DL-bearing mice resulted in a myelopotentiating action, reflected by an elevated count of bone marrow cells (BMC) accompanied by augmented proliferative ability and a declined induction of apoptosis. The BMC of 3-BP-administered mice displayed enhanced responsiveness to macrophage colony-stimulating factor for colony-forming ability of myeloid lineage along with an enhanced differentiation of F4/80+ bone marrow-derived macrophages (BMDM). BMDM differentiated from the BMC of 3-BP-administered DL-bearing mice showed an augmented response to lipopolysaccharide and interferon-γ for activation, displaying an augmented tumor cytotoxicity, expression of cytokines, reactive oxygen species, nitric oxide, CD11c, TLR-4, and HSP70. These features are indicative of the differentiation of M1 subtype of macrophages. Thus, this study demonstrates the myelopotentiating action of 3-BP, indicating its hematopoietic safety and potential for reinforcing the differentiation of macrophages in a tumor-bearing host.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Piruvatos/uso terapêutico , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Animais , Ascite , Células da Medula Óssea , Diferenciação Celular , Proliferação de Células , Macrófagos , Camundongos Endogâmicos BALB C , Mielopoese/efeitos dos fármacos , Complexo Piruvato Desidrogenase , Timoma/sangue , Neoplasias do Timo/sangueRESUMO
Introduction: Sodium caseinate (CS) and its components (alpha-casein, beta-casein, and kappa-casein) have been shown to inhibit the proliferation of the mouse hematopoietic 32D clone 3 (32Dcl3) cell line and induce its differentiation into macrophages. It is well-known that alpha-casein induces IL-1ß production and that this cytokine inhibits the proliferation via the production of tumor necrosis factor alpha (TNF-alpha), but it is not known if CS and the caseins inhibit the proliferation via TNF-alpha production. Objective: To evaluate if CS and alpha-casein, beta-casein and kappa-casein inhibit the proliferation on 32Dcl3 cell line via TNF-alpha. Materials and methods: We used different concentrations of CS, alpha-casein, betacasein and kappa-casein in 32Dcl3 cells to evaluate cell proliferation. We assessed cell viability by MTT, induction to apoptosis by flow cytometry, and TNF-alpha synthesis by ELISA. Additionally, we performed anti-TNF-alpha neutralization assays on 32Dcl3 cells treated with CS and alpha-casein and we evaluated proliferation. Results: The results showed that CS, alpha-casein, beta-casein, and kappa-casein reduced proliferation of the 32Dcl3 cell line without affecting the viability and that only CS and alpha-casein induced apoptosis and the release of TNF-alpha. The 32Dcl3 cells treated with CS and alpha-casein reestablished their proliferation by using anti-TNF-alpha antibodies. Conclusion: TNF-alpha was the main responsible for the inhibition of proliferation in 32Dcl3 cells treated with CS or alpha-casein.
Introducción. Se ha demostrado que el caseinato de sodio y sus componentes (caseínas α, ß y κ) inhiben la proliferación de la línea celular hematopoyética de ratón 32D clone 3 (32Dcl3) e inducen su diferenciación hacia macrófagos. Se sabe que la caseína α induce la producción de IL-1ß y que esta última citocina inhibe la proliferación celular mediante la producción del factor de necrosis tumoral alfa (TNF-α), pero se desconoce si el caseinato de sodio y las caseínas inducen la producción de TNF y si este es el responsable de la inhibición de la proliferación. Objetivo. Evaluar si el caseinato de sodio y las caseínas α, ß y κ inhiben la proliferación de la línea celular 32Dcl3 mediante la producción de TNF-α. Materiales y métodos. Se usaron diferentes concentraciones de caseinato de sodio y de las caseínas α, ß y κ en las células 32Dcl3. Posteriormente, se evaluaron la viabilidad celular mediante una prueba con el MTT [3-(4,5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol], la inducción de apoptosis con la citometría de flujo y la síntesis del TNF-α con el ELISA. Además, se hicieron pruebas de neutralización con anti-TNF-α en células 32Dcl3 tratadas con caseinato de sodio y caseína α, y se evaluó la proliferación celular. Resultados. Se encontró que el caseinato de sodio y las caseínas α, ß y κ reducían la proliferación de la línea celular 32Dcl3 sin afectar la viabilidad, y que solo el caseinato y la caseína α inducían la apoptosis y la liberación al medio de TNF-α. La proliferación de células 32Dcl3 tratadas con caseinato y caseína α se restableció al usar anticuerpos anti-TNF-α. Conclusión. El TNF-α fue el principal responsable de la inhibición de la proliferación en las células 32Dcl3 tratadas con caseinato de sodio o caseína α.
Assuntos
Caseínas/farmacologia , Células Mieloides/efeitos dos fármacos , Mielopoese/efeitos dos fármacos , Fator de Necrose Tumoral alfa/fisiologia , Animais , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Macrófagos/citologia , Camundongos , Células Mieloides/citologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
OBJECTIVE: Clozapine is the favoured antipsychotic for treatment-refractory schizophrenia, but has a 1%-2% incidence of agranulocytosis. Patients who require chemotherapy therefore pose a unique management dilemma for haematologists, oncologists and psychiatrists. METHODS: The Ovid MEDLINE and EMBASE databases were searched to identify reports describing use of clozapine concurrent with chemotherapy until 31 March 2019. The following terms (with variations) were used: neoplasm, cancer, tumour, malignancy, chemotherapy, antineoplastic and clozapine. RESULTS: Twenty-seven cases were included after reviewing titles and abstracts for relevance. Fifteen patients had solid organ tumours, and 12 had haematological malignancies, including three who underwent autologous haematopoietic stem cell transplantation (AutoHSCT). Clozapine was continued in 14 cases (albeit dose reduced in 2), with a reported median neutropaenic nadir of 0.29 × 109 /L (range 2.2 to <0.0 × 109 /L). Clozapine was discontinued or substituted for another antipsychotic in the remaining 13 cases, all except one of whom experienced marked psychiatric deterioration. The only neutropenia-related complication was one case of bacteraemia with high-dose melphalan conditioning for AutoHSCT. CONCLUSIONS: These findings argue in favour of clozapine continuation during chemotherapy. Further research is needed to develop guidance to minimise the risk of neutropenia-related complications from concurrent treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gerenciamento Clínico , Humanos , Leucocitose/etiologia , Resultado do TratamentoRESUMO
Resumen Introducción. Se ha demostrado que el caseinato de sodio y sus componentes (caseínas α, β y κ) inhiben la proliferación de la línea celular hematopoyética de ratón 32D clone 3 (32Dcl3) e inducen su diferenciación hacia macrófagos. Se sabe que la caseína α induce la producción de IL-1β y que esta última citocina inhibe la proliferación celular mediante la producción del factor de necrosis tumoral alfa (TNF-α), pero se desconoce si el caseinato de sodio y las caseínas inducen la producción de TNF y si este es el responsable de la inhibición de la proliferación. Objetivo. Evaluar si el caseinato de sodio y las caseínas α, β y κ inhiben la proliferación de la línea celular 32Dcl3 mediante la producción de TNF-α. Materiales y métodos. Se usaron diferentes concentraciones de caseinato de sodio y de las caseínas α, β y κ en las células 32Dcl3. Posteriormente, se evaluaron la viabilidad celular mediante una prueba con el MTT [3-(4,5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol], la inducción de apoptosis con la citometría de flujo y la síntesis del TNF-α con el ELISA. Además, se hicieron pruebas de neutralización con anti-TNF-α en células 32Dcl3 tratadas con caseinato de sodio y caseína α, y se evaluó la proliferación celular. Resultados. Se encontró que el caseinato de sodio y las caseínas α, β y κ reducían la proliferación de la línea celular 32Dcl3 sin afectar la viabilidad, y que solo el caseinato y la caseína α inducían la apoptosis y la liberación al medio de TNF-α. La proliferación de células 32Dcl3 tratadas con caseinato y caseína α se restableció al usar anticuerpos anti-TNF-α. Conclusión. El TNF-α fue el principal responsable de la inhibición de la proliferación en las células 32Dcl3 tratadas con caseinato de sodio o caseína α.
Abstract Introduction: Sodium caseinate (CS) and its components (alpha-casein, beta-casein, and kappa-casein) have been shown to inhibit the proliferation of the mouse hematopoietic 32D clone 3 (32Dcl3) cell line and induce its differentiation into macrophages. It is well-known that alpha-casein induces IL-1β production and that this cytokine inhibits the proliferation via the production of tumor necrosis factor alpha (TNF-alpha), but it is not known if CS and the caseins inhibit the proliferation via TNF-alpha production. Objective: To evaluate if CS and alpha-casein, beta-casein and kappa-casein inhibit the proliferation on 32Dcl3 cell line via TNF-alpha. Materials and methods: We used different concentrations of CS, alpha-casein, beta-casein and kappa-casein in 32Dcl3 cells to evaluate cell proliferation. We assessed cell viability by MTT, induction to apoptosis by flow cytometry, and TNF-alpha synthesis by ELISA. Additionally, we performed anti-TNF-alpha neutralization assays on 32Dcl3 cells treated with CS and alpha-casein and we evaluated proliferation. Results: The results showed that CS, alpha-casein, beta-casein, and kappa-casein reduced proliferation of the 32Dcl3 cell line without affecting the viability and that only CS and alpha-casein induced apoptosis and the release of TNF-alpha. The 32Dcl3 cells treated with CS and alpha-casein reestablished their proliferation by using anti-TNF-alpha antibodies. Conclusion: TNF-alpha was the main responsible for the inhibition of proliferation in 32Dcl3 cells treated with CS or alpha-casein.