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1.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404983

RESUMO

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for several malignant and non-malignant diseases at the cost of serious treatment-related toxicities (TRTs). Recent research on extending the benefits of HSCT to more patients and indications has focused on limiting TRTs and improving immunological effects following proper mobilization and engraftment. Increasing numbers of studies report associations between HSCT outcomes and the expression or the manipulation of G protein-coupled receptors (GPCRs). This large family of cell surface receptors is involved in various human diseases. With ever-better knowledge of their crystal structures and signaling dynamics, GPCRs are already the targets for one third of the current therapeutic arsenal. The present paper assesses the current status of animal and human research on GPCRs in the context of selected HSCT outcomes via a systematized survey and analysis of the literature.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Receptores Acoplados a Proteínas-G/análise , Animais , Células-Tronco Hematopoéticas/citologia , Humanos , Resultado do Tratamento
2.
Nat Commun ; 10(1): 3496, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375680

RESUMO

The timely mobilization of hematopoietic stem and progenitor cells (HSPCs) is essential for maintaining hematopoietic and tissue leukocyte homeostasis. Understanding how HSPCs migrate between bone marrow (BM) and peripheral tissues is of great significance in the clinical setting, where therapeutic strategies for modulating their migration capacity determine the clinical outcome. Here, we identify an epigenetic regulator, Phc2, as a critical modulator of HSPC trafficking. The genetic ablation of Phc2 in mice causes a severe defect in HSPC mobilization through the derepression of Vcam1 in bone marrow stromal cells (BMSCs), ultimately leading to a systemic immunodeficiency. Moreover, the pharmacological inhibition of VCAM-1 in Phc2-deficient mice reverses the symptoms. We further determine that Phc2-dependent Vcam1 repression in BMSCs is mediated by the epigenetic regulation of H3K27me3 and H2AK119ub. Together, our data demonstrate a cell-extrinsic role for Phc2 in controlling the mobilization of HSPCs by finely tuning their bone marrow niche.


Assuntos
Movimento Celular/genética , Repressão Epigenética , Células-Tronco Hematopoéticas/imunologia , Complexo Repressor Polycomb 2/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Transplante de Medula Óssea/efeitos adversos , Movimento Celular/imunologia , Células Cultivadas , Metilação de DNA/imunologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histonas/genética , Histonas/metabolismo , Camundongos , Camundongos Knockout , Modelos Animais , Complexo Repressor Polycomb 2/genética , Cultura Primária de Células , Molécula 1 de Adesão de Célula Vascular/antagonistas & inibidores
3.
Eur J Haematol ; 103(2): 134-136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140644

RESUMO

Checkpoint inhibitor therapy is effective in the treatment of relapsed classical Hodgkin's Lymphoma. Here, we report a patient with relapsed Hodgkin's Lymphoma who received nivolumab prior to autologous stem cell mobilization. She went on to develop cytokine storm shortly following transplantation, with marked T-cell proliferation coincident with myeloid engraftment. Non-cardiogenic pulmonary edema and alveolar hemorrhage developed despite corticosteroid therapy. There was rapid and complete resolution of these complications with parenteral ascorbic acid infusion. Our case illustrates the risk of cytokine release syndrome following infusion of stem cells mobilized after checkpoint inhibitor therapy and the role of ascorbic acid in its management.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Doença de Hodgkin/complicações , Doença de Hodgkin/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Ácido Ascórbico/administração & dosagem , /tratamento farmacológico , Gerenciamento Clínico , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/diagnóstico , Humanos , Imuno-Histoquímica , Imunofenotipagem , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Condicionamento Pré-Transplante
4.
Int J Hematol ; 110(1): 115-118, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30989487

RESUMO

Autologous stem-cell transplantation is an effective procedure for the treatment of multiple myeloma, and involves the collection of hematopoietic stem cells (HSCs). However, in some patients, HSCs in the bone marrow fail to mobilize. Pomalidomide upregulates CXCR4 in hematopoietic stem cells, in a manner similar to that of lenalidomide, and is, thus, likely to have a negative impact on hematopoietic stem-cell mobilization in multiple myeloma patients. Here, we report the two cases in which hematopoietic stem cells were mobilized using plerixafor plus granulocyte-colony stimulating factor after exposure to lenalidomide and pomalidomide. Use of plerixafor with a sufficient washout period may lead to successful mobilization following pomalidomide use, although further study of this potential use is needed.


Assuntos
Quimioterapia Combinada/métodos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Transplante Autólogo
5.
Vox Sang ; 114(3): 275-282, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30873634

RESUMO

BACKGROUND AND OBJECTIVES: Mobilization of CD34+ cells by stimulation with G-CSF shows considerable variation across stem cell donors. Upfront prediction of CD34+ cell counts in peripheral blood based on easily available steady-state parameters would be helpful for the planning of apheresis and stem cell transplantation. Commonly accepted steady-state predictors for the mobilization are gender, body mass index and platelet count. The aim of the study was the identification of novel predictors that might influence mobilization efficacy and to create a model for the prediction of stem cell mobilization. METHODS: A total of 333 healthy stem cell donors who donated peripheral stem cells in our institution were retrospectively analysed. All available data before stem cell mobilization with G-CSF were included in the database. Primary end-point was CD34+ cell count before the first apheresis. RESULTS: In this cohort cholinesterase, differential blood cell counts including platelets, gender and body mass index were significantly correlated with CD34+ cell count. G-CSF dose per lean body weight showed a significant correlation with mobilization efficacy in women but not in men. A multivariate analysis identified gender, cholinesterase and platelet and red cell count as main predictors of mobilization. Red cell count showed a strong gender dependence, with higher predictive value in females. CONCLUSION: The counts of eosinophils, platelets, red cells, cholinesterase and gender are the most important predictors of CD34+ cell mobilization in our deduced models. The red cell count as a predictor for mobilization showed a differential gender dependence.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/normas , Células-Tronco de Sangue Periférico/metabolismo , Adulto , Antígenos CD34/metabolismo , Colinesterases/metabolismo , Contagem de Eritrócitos , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco de Sangue Periférico/citologia , Contagem de Plaquetas , Fatores Sexuais , Doadores de Tecidos/estatística & dados numéricos
7.
J Clin Apher ; 34(4): 461-467, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30817045

RESUMO

INTRODUCTION: Autologous bone marrow transplantation is a component of the malignant hemopathy therapy. The preferred mobilization and collection method is apheresis. The aim of this study is to compare three protocols analyzing the effect of plerixafor, higher dose of G-CSF and large volume leukapheresis (LVL). MATERIALS AND METHODS: A retrospective cohort study including 119 patients referred for mobilization. Three protocols were compared: (a) G-CSF 10 µg/kg/day subcutaneous (sc) × 4 days mobilizing 1 to 1.5 blood volumes. (b) G-CSF 10 µg/kg/day sc × 4 days + plerixafor 0.24 mg/kg/day sc preventively or as a rescue agent mobilizing 1 to 1.5 blood volumes. (c) G-CSF 20 µg/kg/day sc × 4 days ± plerixafor 0.24 mg/kg/day sc preventively or as a rescue agent mobilizing 3 to 4 blood volumes. RESULTS: The average number of days of apheresis was reduced to 1.37 with protocol 3. The average cost per patient was reduced by 67% compared with protocol 2 and increased by only 5% compared with protocol 1, reducing the failure rate to 0%. CONCLUSION: Adding preemptive or rescue plerixafor (protocol 2) to G-CSF 10 µg/kg/day alone (protocol 1) did not improve the days of apheresis nor the number of CD34+ cells collected but had higher cost and failure rate. Using LVL, plerixafor and G-CSF 20 µg/kg/day (protocol 3) decreased the number of sessions to 1.37, reduced the failure rate to 0% and led to a significant increase in the number of CD34+ cells collected without toxicity and with a similar cost to protocol 1.


Assuntos
Remoção de Componentes Sanguíneos/economia , Protocolos Clínicos/normas , Custos e Análise de Custo , Mobilização de Células-Tronco Hematopoéticas/economia , Adulto , Idoso , Antígenos CD34/análise , Remoção de Componentes Sanguíneos/métodos , Volume Sanguíneo , Estudos de Coortes , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
8.
Med Sci Monit ; 25: 928-936, 2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30710072

RESUMO

BACKGROUND Endothelial injury is the early pathological change of cerebral aneurysm (CA) formation. In addition to its lipid-lowering activity, atorvastatin (ATR) also reportedly promotes vascular repair via mobilizing endothelial progenitor cells (EPC). Here, we investigated the influence of ATR on vascular worsening after CA induction in rats. MATERIAL AND METHODS Adult male Sprague-Dawley rats were randomly assigned to 3 groups: a control (CTR) group, a CA group, and a CA+ATR treatment group. Circulating EPC level and hematological and lipid profiles were measured 3 months after CA induction. Verhoeff-Van Gieson staining and transmission electron microscopy were performed to assess pathological changes in the artery wall. RT-PCR was also performed to evaluate the expression of inflammation-related genes in the aneurysmal wall. RESULTS ATR significantly restored the impaired level of circulating EPC without changing hematological and lipid profiles 3 months after CA induction. ATR markedly inhibited endothelial injury, media thinning, and CA enlargement, accompanied by reduced vascular inflammation. CONCLUSIONS Our preliminary results demonstrate that the mobilization of EPC and improvement of endothelial function by ATR contribute to the prevention of cerebral aneurysm. Further studies are warranted to investigate the detailed mechanism.


Assuntos
Atorvastatina/metabolismo , Aneurisma Intracraniano/patologia , Animais , Atorvastatina/farmacologia , Movimento Celular , Modelos Animais de Doenças , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/patologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/prevenção & controle , Masculino , Substâncias Protetoras/metabolismo , Ratos , Ratos Sprague-Dawley
9.
BMC Cancer ; 19(1): 59, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642286

RESUMO

BACKGROUND: For successful autologous stem cell transplantation, the collection of a sufficient number of hematopoietic stem cells after induction therapy is essential for transplant candidates with multiple myeloma (MM). METHODS: In this study, we compared the efficacy and safety of stem cell mobilization using cyclophosphamide (CY; 3.0 g/m2 on day 1) or etoposide (VP-16; 375 mg/m2 on days 1 and 2) in patients with MM. Granulocyte-colony stimulating factor (G-CSF, 10 µg/kg/day, subcutaneously) was administered from the onset of neutropenia to the final day of collection. RESULTS: Sixty-five patients were mobilized with a combination of CY and G-CSF, and 63 were mobilized with a combination of VP-16 and G-CSF. All patients were mobilized within 7 months of beginning frontline treatment. The median number of CD34+ cells collected was significantly higher in the VP-16 mobilization group than in the CY mobilization group (27.6 ×  106 CD34+/kg vs. 9.6 × 106 CD34+/kg, P <  0.001). The rate of mobilization failure, defined as < 2.0 × 106 CD34+/kg collected in three apheresis procedures, was lower in the VP-16 group than in the CY group (1.6% vs. 10.8%, P = 0.062). Severe infections during the mobilization period were more frequent in the CY group than in the VP-16 group (18.5% vs. 7.9%, P = 0.117). CONCLUSION: In conclusion, an intermediate dose of VP-16 with G-CSF appears to be an effective and tolerable chemo-mobilization method compared to CY and G-CSF, particularly in cases where use plerixafor in MM is difficult.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico/citologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Feminino , Seguimentos , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Transplante de Células-Tronco de Sangue Periférico/métodos , Células-Tronco de Sangue Periférico/metabolismo , Prognóstico , Resultado do Tratamento
10.
J Clin Apher ; 34(1): 39-43, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30426567

RESUMO

BACKGROUND: Mobilization regimen choice is a significant contributing factor for successful hematopoietic progenitor cell (HPC) collection by leukocytapheresis and reaching the target CD34+ cell dose. How mobilization regimen affects collection efficiency and the quality of products collected using the Spectra Optia apheresis instrument is not fully known. METHODS: We evaluated the impact of granulocyte-colony stimulating factor (GCSF) and GCSF/plerixafor mobilization regimens on CE and product composition. We studied 373 leukocytapheresis HPC collections for 147 autologous transplants from January 1, 2010 to December 31, 2014. Patients were categorized in two groups; good mobilizers, mobilized with GCSF only (GM) and poor mobilizers, mobilized with GCSF and Plerixafor (PM). RESULTS: Overall, compared with PM group, total nucleated cell (TNC) yield was significantly lower in GM group (P = <.001). In contrast, median percent mononuclear cell (MNC) collected from GM (86.5%) was significantly higher than products collected from PM group (79.5%; P < .001). Compared with GM group, CD34+ cell CE was about 10% lower in PM group (P < .008). In addition, daily CD34+ cell/Kg yield was significantly higher in GM (2.08 × 10/Kg) compared with PM group (1.64 x 10/Kg, P = .019). Overall, the median number of collections per patient was two for GM and three for PM (P = .004). CONCLUSION: Products collected from PM group contained higher TNC content relative to GM group but had lower MNC enrichment, CD34+ cell CE and daily CD34+ cell yield per Kg.


Assuntos
Antígenos CD34/sangue , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Controle de Qualidade , Adulto , Autoenxertos , Contagem de Células , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Granulócitos/citologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Leucaférese , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade
11.
Transfusion ; 59(1): 316-324, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548284

RESUMO

BACKGROUND: Plerixafor (PFX) mobilizes CD34+ cells into circulation by disrupting the CXCR4 binding of the hematopoietic stem cell in its bone marrow niche. STUDY DESIGN AND METHODS: in the prospective HOVON-107 study (www.hovon.nl) 23 allogeneic HLA-identical sibling donors received one or two subcutaneous (sc) injections of plerixafor 0.320 mg/kg.The primary endpoint, was defined as feasibility to mobilize a minimum of 2.0 x106 CD34+ cells/kg recipient weight obtained by leukopheresis in at least 90% of the donors. RESULTS: median 3.3 x 106 CD34+ cells/kg (1.9-6.5) were collected after 1 (n=12) or 2 (n=10) sc injections of PFX. Side effects occurred in 15/23 (65%) donors: most were grade 1-2; in 5 donors grade 3 and all resolved. All grafts were directly transplanted. Compared to 10 grafts obtained with G-CSF the number of CD34+ cells was 2.4 fold lower but the percentage of phenotypically most immature CD34+ subset was higher (31% vs 15%). The total number of CD3+ cells in the graft seemed higher after PFX-mobilization, but CD4/CD 8 ratios, and frequencies of Th2, Th17 and regulatory T-cells or NK cells were comparable. All patients engrafted and no increase in incidence or severity of acute or chronic graft versus host disease was observed. CONCLUSION: stem cell mobilization with sc PFX 0.320 mg/kg in allogeneic sibling donors is feasible with limited toxicity for donors. 14 allogeneic donors were mobilized with PFX 0.320 mg intravenously according to the same protocol. Due to the limited numbers, these results are in the supplementary section.


Assuntos
Compostos Heterocíclicos/uso terapêutico , Células-Tronco de Sangue Periférico/citologia , Adulto , Aloenxertos , Antígenos CD34/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Irmãos , Adulto Jovem
12.
Transfusion ; 59(2): 659-670, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30537213

RESUMO

BACKGROUND: Previous prediction algorithms to achieve target CD34+ goals have not been widely adopted, with many centers still using a set volume to process for hematopoietic progenitor cell collections. This may be because previous algorithms are challenging to implement. Additionally, no study has yet examined the utility of adjusting the collect flow rate (CFR) based on the donor's preprocedure total mononuclear cell (MNC) count, which correlates with CD34+ yield. STUDY DESIGN AND METHODS: In this retrospective analysis of mobilized allogeneic donors collected using MNC (COBE Spectra, Terumo BCT) or continuous mononuclear cell collection (CMNC) (Spectra Optia, Terumo BCT) procedures, we validated a one-step prediction algorithm to achieve the target CD34+ product dose (Appendix S1, available as supporting information in the online version of this paper). The COBE Spectra MNC Collect Flow Tool (Appendix S2, available as supporting information in the online version of this paper) was used to select the collect flow rate for both MNC and CMNC procedures. Procedural collection efficiency (CE) was compared to that of historical procedures utilizing fixed CFRs (1.0-1.5 mL/min). RESULTS: Ninety-three percent of collections achieved the target CD34+ goal using our algorithm-calculated process volumes. The remaining 7% of cases had CEs lower than the algorithm CE (0.40), and thus were below goal. Second, an MNC-based CFR improved MNC and CD34+ CEs in patients with higher MNC counts compared to our historical controls. CONCLUSION: We validated that this simple, single-step prediction algorithm achieves the target CD34+ goal in most HPC collections. Secondly, we showed that an MNC-based CFR for hematopoietic progenitor cell collections improves CE at higher MNCs; this may be preferable to a WBC-based CFR because of variability of MNC counts at a given WBC count.


Assuntos
Algoritmos , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas , Leucócitos Mononucleares , Doadores de Tecidos , Adolescente , Adulto , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Exp Hematol ; 70: 1-9, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30428338

RESUMO

Granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood progenitor cells (G-PBs) from either a related or unrelated donor continue to be the preferred donor source for most allogeneic hematopoietic cell transplantation (HCT). Recently, the American Society for Blood and Marrow Transplantation has recommended marrow instead of G-PBs as an unrelated graft source due to its lower rate of chronic graft-versus-host disease (cGVHD). However, the use of marrow is limited by both clinical considerations (slower rate of engraftment and increased donor morbidity) and logistical considerations (use of operating room resources and increased physician utilization), so this recommendation has not been widely adopted. An optimal donor source would include the rapid engraftment characteristic and the low donor morbidity associated with G-PBs and a rate of cGVHD similar to or lower than that of marrow. Recent data suggest that plerixafor mobilized PBs (P-PBs) have the rapid engraftment characteristics of G-PBs in allogeneic HCT with less cGVHD. The biologic mechanism of the lower rate of cGVHD appears to be through mobilization of regulator natural killer cells and plasmacytoid dendritic cell precursors that are associated with lower acute and chronic GVHD compared with G-PBs and rapid engraftment characterized by rapid myeloid-repopulating capacity. We suggest that, based on the experience of the two Phase II clinical trials and the unique biology of plerixafor-mobilized donor product, it should be evaluated in Phase III trials as an approach to replacing G-CSF mobilization for allogeneic HCT.


Assuntos
Filgrastim/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico , Aloenxertos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos
14.
Leukemia ; 33(3): 749-761, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30254339

RESUMO

Mobilization of hematopoietic stem cells (HSCs) from bone marrow (BM) to peripheral blood (PB) by cytokine granulocyte colony-stimulating factor (G-CSF) or the chemical antagonist of CXCR4, AMD3100, is important in the treatment of blood diseases. Due to clinical conditions of each application, there is a need for continued improvement of HSC mobilization regimens. Previous studies have shown that genetic ablation of the Rho GTPase Cdc42 in HSCs results in their mobilization without affecting survival. Here we rationally identified a Cdc42 activity-specific inhibitor (CASIN) that can bind to Cdc42 with submicromolar affinity and competitively interfere with guanine nucleotide exchange activity. CASIN inhibits intracellular Cdc42 activity specifically and transiently to induce murine hematopoietic stem/progenitor cell egress from the BM by suppressing actin polymerization, adhesion, and directional migration of stem/progenitor cells, conferring Cdc42 knockout phenotypes. We further show that, although, CASIN administration to mice mobilizes similar number of phenotypic HSCs as AMD3100, it produces HSCs with better long-term reconstitution potential than that by AMD3100. Our work validates a specific small molecule inhibitor for Cdc42, and demonstrates that signaling molecules downstream of cytokines and chemokines, such as Cdc42, constitute a useful target for long-term stem cell mobilization.


Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
15.
Blood Adv ; 2(19): 2505-2512, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30282642

RESUMO

Novel therapies for sickle cell disease (SCD) based on genetically engineered autologous hematopoietic stem and progenitor cells (HSPCs) are critically dependent on a safe and effective strategy for cell procurement. We sought to assess the safety and efficacy of plerixafor when used in transfused patients with SCD for HSC mobilization. Six adult patients with SCD were recruited to receive a single dose of plerixafor, tested at lower than standard (180 µg/kg) and standard (240 µg/kg) doses, followed by CD34+ cell monitoring in peripheral blood and apheresis collection. The procedures were safe and well-tolerated. Mobilization was successful, with higher peripheral CD34+ cell counts in the standard vs the low-dose group. Among our 6 donors, we improved apheresis cell collection results by using a deep collection interface and starting apheresis within 4 hours after plerixafor administration. In the subjects who received a single standard dose of plerixafor and followed the optimized collection protocol, yields of up to 24.5 × 106 CD34+ cells/kg were achieved. Interestingly, the collected CD34+ cells were enriched in immunophenotypically defined long-term HSCs and early progenitors. Thus, we demonstrate that plerixafor can be employed safely in patients with SCD to obtain sufficient HSCs for potential use in gene therapy.


Assuntos
Anemia Falciforme/terapia , Remoção de Componentes Sanguíneos , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/administração & dosagem , Adolescente , Adulto , Relação Dose-Resposta a Droga , Terapia Genética/métodos , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Imunofenotipagem , Transplante de Células-Tronco de Sangue Periférico/métodos , Projetos Piloto , Adulto Jovem
16.
Transfus Apher Sci ; 57(5): 623-627, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30268541

RESUMO

Mobilization failure is a major concern in patients undergoing hematopoietic cell transplantation, especially in an autologous setting, as almost all donor harvests can be accomplished with granulocyte-colony stimulating factor (G-CSF) alone. Poor mobilizers, defined as those with a peripheral blood CD34+ cell count ≤20 cells/µl after mobilization preceding apheresis is a significant risk factor for mobilization failure. We recommend preemptive plerixafor plus G-CSF (filgrastim, 10 µg/kg daily) as a first mobilization strategy, which yields sufficient peripheral blood progenitor cells (PBPCs) in almost all patients and avoids otherwise unnecessary remobilization. Preemptive plerixafor is administered in patients with a day-4 peripheral blood CD34+ count <15, depending on the disease and the target PBPC amount. Cyclophosphamide is reserved for patients who fail the first PBPC collection. We recommend second mobilization for patients who could not achieve a sufficient PBPC amount with the first mobilization. In these patients, a second attempt with plerixafor plus G-CSF or mobilization with plerixafor in combination with cyclophosphamide and G-CSF is recommended. Increased dose and/or twice daily administration of G-CSF can be considered.


Assuntos
Fator Estimulador de Colônias de Granulócitos/metabolismo , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos
17.
Cells Tissues Organs ; 206(1-2): 26-34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30257252

RESUMO

OBJECTIVE: To investigate the mobilization of peripheral blood mesenchymal stem cells (PBMSCs) and whether a combination of PBMSCs and modified demineralized bone matrix (DBM) promoted the repair of cartilage lesions in a pig model. METHODS: Pig PBMSCs were mobilized by the combined administration of granulocyte colony-stimulating factor (G-CSF) and the CXCR4 antagonist AMD3100. Colony formation was detected by the fibroblast colony-forming unit (CFU-F) count and the percentage of the CD45-CD90+ cell population by flow cytometry. The mobilized cells were identified as MSCs by their morphological characteristics, surface markers, and differentiation potentials. The composite scaffolds carrying BMP-2 and TGF-ß3 chitosan sustained-release microspheres/DBM were prepared by emulsion cross-linking and the Urist method, and scanning electron microscopy (SEM) observation was performed. The model of pig cartilage defect was prepared, and gross observation, histological examination, immunohistochemistry, and O'Driscoll scoring were performed 4, 8, and 12 weeks postoperation. RESULTS: After mobilization, the number of CFU-Fs in the peripheral blood in the experimental group (G-CSF + AMD3100) was significantly increased compared with the control group (p < 0.05). The proportion and total number of CD45-CD90+ cells were increased (p < 0.05). The mobilized stem cells had MSC characteristics. SEM of the new tissue-engineered cartilage showed that PBMSCs were evenly grown on the surface of the scaffold and microsphere morphology had no obvious change. Gross observation, histological examination, immunohistochemistry, and O'Driscoll score were better in the experimental group than in the other groups (p < 0.05). CONCLUSION: G-CSF + AMD3100 is an effective mobilization agent for PBMSCs. The new tissue-engineering cartilage constructed by two-factor sustained-release microspheres/DBM composite PBMSCs effected good repair of the cartilage defect in pigs.


Assuntos
Matriz Óssea/química , Condrogênese , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Proteína Morfogenética Óssea 2/administração & dosagem , Proteína Morfogenética Óssea 2/farmacologia , Cartilagem Articular/lesões , Células Cultivadas , Condrogênese/efeitos dos fármacos , Preparações de Ação Retardada/química , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Suínos , Fator de Crescimento Transformador beta3/administração & dosagem , Fator de Crescimento Transformador beta3/farmacologia
18.
Ann Surg ; 268(4): 620-631, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30102635

RESUMO

INTRODUCTION: Acute liver failure (ALF) affects 2000 Americans each year with no treatment options other than liver transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rodents. The objective of this study was to assess whether stem cell mobilizing drugs are lifesaving in a large animal preclinical model of ALF, to assess readiness for a clinical trial. METHODS: Male Yorkshire pigs (14-18 kg) were divided into 2 groups, control (n = 6) and treatment (n = 6). All pigs received an intravenous bolus of the hepatotoxin D-galactosamine (0.5 g/kg) via central line and were followed up until death or day 28. Treated animals received simultaneous intramuscular injection of plerixafor (1 mg/kg) and G-CSF (2 µg/kg) at baseline, 24 and 48 hours after toxin infusion to mobilize endogenous stem cells, as previously described. Control animals received saline. RESULTS: All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by clinical, biochemical, and histopathological evidence of ALF. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by a mean of 4× in the treated group at the peak of mobilization (P = 0.0004). CONCLUSIONS: Stem cell mobilizing drugs were lifesaving in a preclinical large animal model of ALF. Since no therapeutic options other than liver transplantation are currently available for critically ill patients with ALF, a multicenter clinical trial is warranted.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacologia , Falência Hepática Aguda/tratamento farmacológico , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Galactosamina , Imuno-Histoquímica , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Suínos
19.
Int J Hematol ; 108(5): 524-534, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30043330

RESUMO

The present study (ClinicalTrials.gov Identifier: NCT02221492) was conducted to assess the efficacy and safety of plerixafor for the mobilization and collection of haematopoietic stem cells (HSCs) for autologous transplantation in Japanese non-Hodgkin lymphoma (NHL) patients. In this randomized phase 2 study, patients received granulocyte-colony stimulating factor (G-CSF, filgrastim) 400 µg/m²/day for up to 8 days. Starting on the evening of day 4, patients received, for up to 4 days, either plerixafor (240 µg/kg/day) in the G-CSF+ plerixafor arm (GP arm) or G-CSF alone arm (G arm). On day 5, daily apheresis started and was continued for up to 4 days, or until ≥ 5 × 106 CD34+ cells/kg was collected. A total of 32 patients were randomized to either the GP or G arm. In the GP arm, 9/16 patients (56.3%) achieved collection of ≥ 5 × 106 CD34+ cells/kg in ≤ 4 days of apheresis, while 1/16 patient (6.3%) achieved this target in the G arm. The most common treatment-emergent adverse events in the GP arm were back pain (56.3%), platelet count decreased (25.0%), headache, diarrhoea, and nausea (18.8% each). We found that plerixafor was well tolerated and effective for the mobilization and collection of peripheral HSCs for autologous transplantation in Japanese NHL patients.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Autoenxertos , Feminino , Compostos Heterocíclicos/efeitos adversos , Humanos , Linfoma não Hodgkin/sangue , Masculino , Pessoa de Meia-Idade
20.
Cell Transplant ; 27(8): 1249-1255, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29991278

RESUMO

The interaction of SDF-1α (also known as CXCL12) with the CXCR4 receptor plays a critical role in the retention of hematopoietic stem cells (HSCs) in bone marrow. The viral macrophage inflammatory protein-II (vMIP-II), a human herpesvirus-8 (HHV-8)-encoded viral chemokine, can bind the CXCR4 receptor and inhibit endogenous ligand-induced calcium responses and cell migration. Previously, we used the bivalent ligand approach to link synthetically two unnatural D-amino acid peptides derived from the N-terminus of vMIP-II (DV1 and DV3, respectively) to generate a dimeric peptide, DV1-K-(DV3) (also named HC4319), which shows very high affinity for CXCR4. Here, we studied the biological effects of this dimeric peptide, HC4319, and its monomeric counterpart, DV1, on SDF-1α-induced signaling in CXCR4- or CXCR7-transfected Chinese hamster ovary cells and mobilization of hematopoietic progenitor cells (HPCs) in C3H/HeJ mice using an HPC assay. HC4319 and DV1 inhibited significantly the phosphorylation of Akt and Erk, known to be downstream signaling events of CXCR4. This in vivo study in C3H/HeJ mice showed that HC4319 and DV-1 strongly induced rapid mobilization of granulocyte-macrophage colony-forming units (CFUs), erythrocyte burst-forming units, and granulocyte-erythrocyte-monocyte-megakaryocyte CFUs from the bone marrow to the blood. These results provide the first reported experimental evidence that bivalent and D-amino acid peptides derived from the N-terminus of vMIP-II are potent mobilizers of HPCs in C3H/HeJ mice and support the further development of such agents for clinical application.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Peptídeos/metabolismo , Receptores CXCR4/metabolismo , Animais , Células CHO , Cricetulus , Células-Tronco Hematopoéticas/citologia , Ligantes , Camundongos , Camundongos Endogâmicos C3H
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