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Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.
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Carcinogénesis , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Esófago , Homeostasis , Proteína Jagged-1 , Proteína Jagged-2 , Células Madre , Animales , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Esófago/patología , Esófago/metabolismo , Células Madre/metabolismo , Ratones , Proteína Jagged-2/metabolismo , Proteína Jagged-2/genética , Humanos , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Ratones Noqueados , Transducción de Señal , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Receptores Notch/metabolismo , Receptores Notch/genética , Diferenciación Celular , Masculino , FemeninoRESUMEN
Under the sustained exposure to tumor microenvironment, effector lymphocytes may transform into the suppressive populations. γδ T cells are recognized as a crucial mediator and effector of immune surveillance and thereby a promising candidate for anti-tumor immunotherapy. Emerging clinical studies implicate that some γδ T subsets play an important role in promoting tumor progression. Our previous study identified an abnormal Vδ2+ T cells subset with regulatory features (Reg-Vδ2) in the patients with newly diagnosed acute myeloid leukemia (AML), and demonstrated that Reg-Vδ2 cells significantly suppressed the anti-AML effects of effector Vδ2 cells (Eff-Vδ2). The molecular mechanism underlying the subset transformation of Vδ2 cells remains unclear. Here, we found that the expression and activity of STAT5 were significantly induced in Reg-Vδ2 cells compared with Eff-Vδ2 cells, which was consistent with the differences found in primary Vδ2 cells between AML patients and healthy donors. In-vitro experiments further indicated that STAT5 was required for the induction of Reg-Vδ2 cells. The combined immunophenotypical and functional assays showed that blockage of STAT5 alleviated the immunosuppressive effect of Reg-Vδ2 cells on Eff-Vδ2 cells and enhanced the anti-AML capacity of Vδ2 cells from health donors and AML patients. Collectively, these results suggest that STAT5 acts as a critical regulator in the transformation of effector Vδ2 cells into a subset with immunosuppressive characteristics, providing a potential target for the improvement the efficacy of γδ T cells-based immunotherapy to treat AML and other hematologic malignancies.
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Leucemia Mieloide Aguda , Subgrupos de Linfocitos T , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Factor de Transcripción STAT5/metabolismo , Microambiente TumoralRESUMEN
Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.
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Carcinoma de Células Escamosas , Transducción de Señal , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Homeostasis , Transducción de Señal/genética , Células Madre/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Señalizadoras YAPRESUMEN
Transition metal chalcogenides (TMCs) are recognized as highly efficient electrocatalysts and have wide applications in the field of hydrogen production by electrolysis of water, but the real catalytic substances and catalytic processes of these catalysts are not clear. The species evolution of Mo and Se during alkaline hydrogen evolution was investigated by constructing MoSe2@CoSe2 heterostructure. The real-time evolution of Mo and Se in MoSe2@CoSe2 was monitored using in situ Raman spectroscopy to determine the origin of the activity. Mo and Se in MoSe2@CoSe2 were dissolved in the form of MoO42- and SeO32-, respectively, and subsequently re-adsorbed and polymerized on the electrode surface to form new species Mo2O72- and SeO42-. Theoretical calculations show that adsorption of Mo2O72- and SeO42- can significantly enhance the HER catalytic activity of Co(OH)2. The addition of additional MoO42- and SeO32- to the electrolyte with Co(OH)2 electrodes both enhances its HER activity and promotes its durability. This study helps to deepen our insight into mechanisms involved in the structural changes of catalyst surfaces and offers a logical basis for revealing the mechanism of the influence of species evolution on catalytic performance.
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Acute myeloid leukemia (AML) patients can benefit from allogeneic hematopoietic cell transplantation (alloHCT) and achieve long-term remission. Recovery of T cell quantity and quality is critical to reduce the incidences of life-threatening complications after alloHCT. Although the general recovery level of γδ T cells is recognized to be associated with outcomes of patients who suffered from various hematological diseases and received alloHCT, the correlation between γδ T cell subsets and the prognosis in AML patients following transplantation remains to be investigated. In the current study, the recoveries of T cell subpopulations in 103 AML patients were dissected at different time points after haploidentical HCT (haploHCT). Statistical analyses showed that the absolute number of Vδ2+ T cells on day 90 was an independent risk factor for predicting 2-year OS in AML patients following haploHCT. The survival advantage from the improved recovery of day-90 Vδ2+ T cells was attributed to reducing the infection-related mortality. Consistently, lower 2-year non-relapse mortality was found in recipients with higher day-90 levels of Vδ2+ T cells. Notably, day-270 Vδ2+ T cell numbers reversely correlated to both 2-year and 5-year probabilities of relapse in this scenario. These results highlighted the significant correlation of Vδ2+ T cells recovery with long-term survival and relapse after alloHCT, suggesting that Vδ2+ T cells-based immune strategies may help control infectious complications and leukemia recurrence in AML patients.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Trasplante Homólogo , Incidencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Recurrencia , Enfermedad CrónicaRESUMEN
Description of immune landscapes in malignant microenvironment is critical to the improvement of therapeutic strategies for various tumors. Acute myeloid leukemia (AML) remains a severe life-threatening malignancy and often confronts treatment dilemma in clinic. Although γδ T cells exhibit independent and potent cytotoxicity against leukemic cells in vitro and in the mouse models, efficacy of γδ T cell-based immunotherapy on AML patients has seemed unsatisfying so far. How the anti-AML capacity of γδ T cells is suppressed in vivo remains elusive. Herein, we found an aberrant γδ T cells subset expressing CD25+CD127lowVδ2+ in the bone marrows of patients with newly diagnosed AML. The emergence of this subset was significantly associated with disease status and risk stratification as well as with the abnormally increased bone morphogenetic protein 2 (BMP2). Mechanistically, BMP2 could directly induce CD25+CD127lowVδ2+ γδ T cells (named as Reg-Vδ2) in vitro. The immunosuppressive features of Reg-Vδ2 cells were identified by combining immunophenotypical and functional data. Furthermore, inhibition of BMP2 pathway significantly blocked the emergence of Reg-Vδ2 cells and enhanced the anti-AML immunity in humanized mice. These findings not only provide a novel insight into the mechanisms of immunosuppression in the context of leukemia, but also suggest potential targets for the treatment of AML and other hematopoietic malignancies.
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Linfocitos Intraepiteliales , Leucemia Mieloide Aguda , Linfocitos T , Animales , Ratones , Proteína Morfogenética Ósea 2 , Tolerancia Inmunológica , Linfocitos Intraepiteliales/metabolismo , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Microambiente Tumoral , Linfocitos T/inmunologíaRESUMEN
Relapse and refractoriness remain the major obstacles in clinical treatment of acute myeloid leukemia (AML). Efficacy of current therapeutic strategies for relapsed/refractory (R/R) AML is generally unsatisfying. Vδ2+ T cells have become an attractive candidate for immunotherapy of various types of tumors. However, the results were not exciting in some pilot studies utilizing Vδ2 cell-based protocols to treat R/R AML. Functional receptors on Vδ2 cells and immunogenic ligands on leukemia cells are both critical to the anti-AML effect of Vδ2 cells, which have not been characterized in the context of R/R AML. CD277 can bind to phosphoantigens and promote the activation of Vδ2 cells. Anti-CD277 (clone 20.1) monoclonal antibody (20.1 mAb) has been identified as an agonist of CD277. Whether 20.1 mAb sensitizes R/R AML cells awaits investigation. Herein, we showed that the expressions of activating receptors on Vδ2 cells and CD277 on leukemia cells were deficient in patients with R/R AML. While agonists for NKG2D and TRAIL ligands did not increase the immunogenicity of R/R AML cells, 20.1 mAb significantly enhanced the cytotoxicity of Vδ2 cells on the drug-resistant human AML cell line and different types of primary AML cells from R/R patients. The sensitizing effect of 20.1 mAb was dependent on inducing degranulation of Vδ2 cells. These findings suggest a decisive role of CD277 in mediating the recognition of R/R AML cells by Vδ2+ T cells. CD277 agonist combining adoptive transfer of Vδ2+ T cells may improve the efficacy in the treatment of R/R AML.
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Leucemia Mieloide Aguda , Linfocitos T , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Humanos , Inmunoterapia/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Linfocitos T/patologíaRESUMEN
Cytomegalovirus (CMV) reactivation is the most frequent viral infectious complication correlating to non-relapse mortality after allogeneic haematopoietic cell transplantation (alloHCT). The intrinsic anti-CMV immunity has not been completely elucidated. γδ T-cells have drawn increasing attentions due to their distinct biological features and potential ability against viral infections. Previous studies reported a general association of γδ T-cells or Vδ2-negative γδ T-cells with CMV reactivation. Whereas researches for the direct responses and specific functions of γδ T subsets remain limited, especially in the scenario of alloHCT. Herein, we initially demonstrated that Vδ1+ T-cells directly and independently recognized cell-free CMV and CMV-infected target cells, and inhibited CMV replication in vitro. The anti-CMV effect of Vδ1+ T-cells was partially through TCRγδ, TLR2 and NKG2D receptor pathways. Further investigation about the anti-CMV characteristics of Vδ1+ T-cells was performed in a clinical cohort with different CMV reactivation status after alloHCT. We found that occasional CMV reactivation remarkably increased the recovery levels and stimulated the functional activity of Vδ1+ T-cells. Whereas disability of Vδ1+ T-cells was observed upon refractory CMV reactivation indicating the differential responses of Vδ1+ T-cells under different CMV reactivation status. CXCL10 and IFN-ß that were dramatically induced by occasional CMV reactivation could re-activate the deficient Vδ1+ T-cells from recipients with refractory CMV reactivation. These findings unveiled the distinct activities of Vδ1+ T-cells in anti-CMV immunity after alloHCT and may help develop novel strategies for the treatment of CMV infectious diseases.
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Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Subgrupos de Linfocitos T , Activación Viral , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Subfamilia K de Receptores Similares a Lectina de Células NK , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/citología , Receptor Toll-Like 2RESUMEN
Polydimethylsiloxane (PDMS), as the benchmark of organophilic membrane materials, still faces challenges for removal of aromatic compounds due to the undesirable transport channels. In this work, we propose to reconstruct the PDMS conformation with tunable side group mobility by introducing phenyl as rigid molecular spacer to relieve steric hindrance of large-sized aromatic molecules; meanwhile, polymer segments are loosely stacked to provide additional degrees of freedom as increasing the permeant size. Moreover, the reconstructed PDMS is engineered into the composite membrane with prevention of condensation of aromatic compounds in the substrate pores. The resulting thin-film composite membrane achieved one order of magnitude higher flux (11.8â kg m-2 h-1 ) with an equivalent separation factor (12.3) compared with the state-of-the-art membranes for aromatic removal. The permeant-customized membrane molecular and microstructure designing strategy opens a new avenue to develop membranes for specific separation targets.
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Chitooligosaccharide-zinc (COS·Zn) is a powerful anti-oxidant and anti-aging scavenger, whose anti-oxidative ability immensely exceeds vitamin C. Therefore, this study was aimed to investigate the protective effects of COS·Zn against premature ovarian failure (POF) and potential mechanisms. Female KM adult mice were divided into the following groups: a treatment group (150 mg·kg-1·d-1 COS·Zn), a treatment group (300 mg·kg-1·d-1 COS·Zn), a prevention group, two control groups and two CY/BUS groups. COS·Zn (150, 300 mg·kg-1·d-1) and COS·Zn (300 mg·kg-1·d-1) were therapeutically and preventatively administered to POF mice in the treatment and prevention studies, respectively. All the groups were administered for 21 days. Fewer primary and secondary follicles were observed in the COS·Zn-treated groups (including the treatment and prevention groups) than those of the control groups. Meanwhile, the ovarian index and the levels of FSH and LH notably increased in the treatment and prevention groups compared with those in the CY/BUS group. The levels of MVH, OCT4 and PCNA in the treatment group (300·kg-1·d-1 COS·Zn) and MVH in the prevention group remarkably increased compared with those in the CY/BUS groups. Meanwhile, the levels of P53 and P16 protein were down-regulated in the treatment and prevention groups compared with those in the CY/BUS groups. Additionally, the amounts of Sestrin2 (SESN2) and SOD2 protein were obviously higher in the treatment group (150 mg·kg-1·d-1 COS·Zn) than those in the CY/BUS groups. Similarly, the amounts of NRF2 and SESN2 protein were up-regulated in the prevention group. Besides, an increased GSH level was observed in the two treatment groups, compared with that in the CY/BUS groups, and the same trend was also present in the prevention group. Taken together, COS·Zn improves the ovarian and follicular development through regulating the SESN2/NRF2 signaling pathway. These results suggest the role of COS·Zn as a novel agent for the treatment and prevention of POF.
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Insuficiencia Ovárica Primaria , Animales , Quitosano , Femenino , Humanos , Ratones , Factor 2 Relacionado con NF-E2/genética , Proteínas Nucleares , Oligosacáridos , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Transducción de Señal , ZincRESUMEN
Graft-versus-host disease (GVHD) is a pathology in which chemokines and their receptors play essential roles in directing the migration of alloreactive donor T cells into GVHD organs, thereby leading to further target tissue damage. Currently, acute GVHD (aGVHD) remains a major cause of high morbidity and mortality in patients who underwent allogeneic hematopoietic cell transplantation (alloHCT). The identification of immune cells that correlate with aGVHD is important and intriguing. To date, the involvement of innate-like γδ T cells in the pathogenesis of aGVHD is unclear. Herein, we found that primary human γδ T cells did not directly trigger allogeneic reactions. Instead, we revealed that γδ T cells facilitated the migration of CD4 T cells via the SDF-1-CXCR4 axis. These results indicate indirect regulation of γδ T cells in the development of aGVHD rather than a direct mechanism. Furthermore, we showed that the expression of CXCR4 was significantly elevated in γδ T cells and CD4 and CD8 T cells in recipients who experienced grades II-IV aGVHD after alloHCT. Consistently, CXCR4-expressing γδ T cells and CD4 T cells were induced in the target organs of mice suffering aGVHD. The depletion of γδ T cells in transplant grafts and treatment with AMD3100, an inhibitor of CXCR4 signaling, delayed the onset of aGVHD and prolonged survival in mice. Taken together, these findings suggest a role for γδ T cells in recruiting alloreactive CD4 T cells to target tissues through the expression of CXCR4. Our findings may help in understanding the mechanism of aGVHD and provide novel therapeutic targets.
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Linfocitos T CD4-Positivos/metabolismo , Quimiocina CXCL12/metabolismo , Quimiotaxis de Leucocito , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos Intraepiteliales/metabolismo , Receptores CXCR4/metabolismo , Adolescente , Adulto , Animales , Bencilaminas/farmacología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Ciclamas/farmacología , Modelos Animales de Enfermedad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Linfocitos Intraepiteliales/efectos de los fármacos , Linfocitos Intraepiteliales/inmunología , Masculino , Ratones Endogámicos NOD , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Transducción de Señal , Trasplante Homólogo , Adulto JovenRESUMEN
OBJECTIVE: Based on the theory that long non-coding RNAs (lncRNAs) sponge microRNAs (miRNAs) to engage in cervical cancer development, this work was set out to investigate the possible role of lncRNA taurine upregulated gene 1 (TUG1) and miR-381-3p in the development of cervical cancer. METHODS: TUG1, miR-381-3p and murine double minute 2 (MDM2) expression were measured in cervical cancer tissues and cells. The nexus between TUG1 and clinicopathological features of cervical cancer was discussed. The biological functions of TUG1, miR-381-3p and MDM2 on cervical cancer cell process were interpreted via gain- and loss-of-function experiments. Also, tumor xenograft in nude mice was conducted in vivo. The interactions between TUG1, miR-381-3p and MDM2 were identified. RESULTS: TUG1 and MDM2 raised while miR-381-3p reduced in cervical cancer. TUG1 expression was related to tumor size, differentiation, international federation of gynecology and obstetrics stage and lymph node metastasis of cervical cancer. Restored miR-381-3p, depleted TUG1 or reduced MDM2 decreased viability, colony-forming, migration and invasion abilities, and facilitated apoptosis of cervical cancer cells. Xenografted tumors grew slowly upon injection with restored miR-381-3p and depleted TUG1. TUG1 bound to miR-381-3p and miR-381-3p targeted MDM2. CONCLUSION: On all accounts, this present study provides evidence that silencing TUG1 depressed cervical cancer cell progression through miR-381-3p/MDM2 axis, highlighting a theoretical basis for cervical cancer treatment.
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MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/biosíntesis , ARN Largo no Codificante/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Adulto , Anciano , Animales , Apoptosis/fisiología , Diferenciación Celular/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , Supervivencia Celular/genética , Femenino , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , ARN Largo no Codificante/genética , Activación Transcripcional , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Therapeutic options for Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative diseases (PTLD) are currently limited, accompanying with some off-target toxicities. We previously demonstrated that early recovery of Vδ2+ T cells inversely correlated to EBV reactivation after allogeneic hematopoietic cell transplantation. Studies in vitro and in the mouse models showed the cytotoxic activity of Vδ2+ T cells on EBV-transformed lymphoproliferative cells, but the efficacy was moderate. Bisphosphonate, such as pamidronate (PAM), have been reported as a sensitizer to trigger tumor cells for Vδ2+ T cells recognition. Valproic acid (VPA) has attracted attentions due to its adjuvant anti-tumor effect with chemotherapy or immunotherapy. Whether PAM and VPA facilitate the immunogenicity of EBV-infected cells towards Vδ2+ T cells cytotoxicity remains unknown. Herein, we demonstrated that lower dosage of VPA and/or PAM did not induce apoptosis of EBV-transformed B lymphoblastoid cell lines (EBV-LCLs) or Vδ2+ T cells. Notably, pre-treatment with PAM significantly increased the cell death of EBV-LCLs after co-culture with Vδ2+ T cells at different ratios. Combining treatment with VPA reinforced the sensitizing effect of PAM. This efficacy was through inducing the accumulation of mevalonate pathway intermediates and dependent on the γδ T cell receptor of Vδ2+ T cells. Similar sensitizing effects of PAM and PAM plus VPA were also demonstrated on the primary PTLD cells. These results highlight the roles of PAM and VPA in the enhancement of immune surveillance and expand the fields of these two drugs in the treatment of different types of malignancies.
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Infecciones por Virus de Epstein-Barr/inmunología , Pamidronato/farmacología , Linfocitos T/efectos de los fármacos , Ácido Valproico/farmacología , Células Cultivadas , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Following the extensive use of immunosuppressive drugs in the clinic, immunosuppression-associated side effects have received increasing attention. Epstein-Barr virus (EBV) reactivation and related lymphoproliferative diseases (LPD) are the lethal complications observed after allogeneic hematopoietic cell transplantation (alloHCT). While studies generally suggest an association between immunosuppressants and EBV reactivation, the effects of specific immunosuppressive drugs and which T-cell subsets mediate these correlations are unclear. Vδ2+ T cells are correlated with EBV reactivation after alloHCT. Researchers have not determined whether Vδ2+ T-cell activities are affected by immunosuppressants and thereby facilitate EBV reactivation and related LPD. METHODS: A clinical cohort study of 170 patients with hematopoietic malignancies who received haploidentical hematopoietic cell transplantation (haploHCT) was performed to investigate whether the early cessation of mycophenolate mofetil (MMF) decreases EBV reactivation and related LPD and to determine whether this change is associated with the recovery of Vδ2 + T cells after transplantation. The effects of MMF on the expansion and anti-EBV capacity of Vδ2+ T cells were detected in vitro and in an immunodeficient mouse model. RESULTS: A reduction in the course of MMF significantly improved the recovery of Vδ2+ T cells from 30 to 90 days after haploHCT (p=0.002, p=0.042 and p=0.035, respectively), accompanied by a significant decrease in EBV reactivation (from 26% to 13%, p=0.033) and EBV-LPD (from 10.6% to 2.4%, p=0.029). The day-30 Vδ2+ T level remained an independent factor for EBV reactivation in patients with different MMF durations (p=0.007). In the in-vitro experiments, MMF inhibited Vδ2+ T-cell expansion and its cytotoxicity on EBV-transformed malignant cells. Furthermore, the therapeutic and prophylactic effects of adoptively transferred human Vδ2+ T cells were attenuated by the MMF treatment in immunodeficient mice with EBV-LPD. CONCLUSIONS: These results elucidated a negative effect of immunosuppressants on the anti-EBV capacity of Vδ2+ T cells. Strategies that appropriately relieve the immunosuppression may improve anti-EBV immunity by increasing the activity of Vδ2+ T cells after alloHCT.
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Infecciones por Virus de Epstein-Barr/fisiopatología , Neoplasias Hematológicas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Subgrupos de Linfocitos T/inmunología , Acondicionamiento Pretrasplante/métodos , Animales , Femenino , Neoplasias Hematológicas/patología , Humanos , RatonesRESUMEN
γδ T cells perform antitumor and antiviral effector functions and are involved in both innate and adaptive immunity. Vδ2+ T cells represent the predominant γδ T subset in the peripheral blood of healthy subjects. Vδ2+ T cells can be selectively activated and expanded by phosphoantigens (pAgs). Dendritic cells (DCs), as potent antigen-presenting cells, are capable of mediating pAgs-triggered Vδ2+ T cells expansion. However, the association between DCs and Vδ2+ T cell recovery in the context of hematopoietic stem cell transplantation (HSCT) remains unclear. We previously demonstrated that the recovery of Vδ2+ T cells was hampered and inversely correlated with Epstein-Barr virus (EBV) reactivation in patients undergoing haploidentical HSCT (haploHSCT). Whether Vδ2+ T cells from haploHSCT recipients can be expanded by stimulation with aminobisphosphonates or pAg-presenting DCs is of particular interest. Herein, we showed that Vδ2+ T cells recovered after haploHSCT failed to expand after ex-vivo stimulation with pamidronate. In addition, we found that the recovery of DC subsets was significantly decreased, and the concentration of myeloid DCs (mDCs) correlated significantly with Vδ2+ T cell recovery in the setting of allogeneic HSCT. Furthermore, coculture of peripheral lymphocytes from recipients with monocyte-derived and pamidronate-pretreated autologous or allogeneic DCs induced the successful expansion of Vδ2+ T cells. Of note, allogeneic DCs from third-party donors stimulated a significantly higher efficiency of Vδ2+ T cell expansion than autologous DCs. More importantly, the memory features were well-retained and the cytotoxic cytokines-production capacity was significantly enhanced in the expanded Vδ2+ T cells. Taken together, these results suggest that the frequency and function of DCs are critical for the recovery of Vδ2+ T cells after allogeneic HSCT. The fact that vigorous expansions of Vδ2+ T cells were induced by phosphoantigen-pretreated DCs, especially by allogeneic third-party DCs, provides additional options for the development of individualized immunotherapy strategies that utilize the anti-viral and anti-leukemic effects of γδ T cells in the context of hematopoietic transplantation.
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Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Femenino , Neoplasias Hematológicas/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Herpesvirus Humano 4/inmunología , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Trasplante Homólogo/métodos , Adulto JovenRESUMEN
Epstein-Barr virus (EBV) reactivation remains a life-threatening complication in recipients of a haploidentical haematopoietic stem cell transplantation (haploHSCT). Reconstitution of adaptive T lymphocytes is generally compromised at the early stages following transplant, suggesting an important role of other effector cells in preventing EBV infection. Our previous studies demonstrated that recovery of CD4- CD8- T cells negatively correlated with EBV reactivation after haploHSCT. In this prospective study on 132 adult patients with haematopoietic malignancy, recovery of T-cell subpopulations was characterized post-haploHSCT. We showed that the median counts of peripheral Vδ2 cells were continuously lower in recipients with EBV reactivation compared with controls at 30, 60 and 90 days after haploHSCT (P values: 0·006, <0·001 and 0·019, respectively). Landmark study further indicated that the cumulative incidence of EBV reactivation was significantly decreased in recipients with higher day-30 Vδ2 counts. Activation of Vδ2 cells upon EBV reactivation was accompanied by an induction of cell apoptosis. Cytotoxic effect of Vδ2 cells on EBV-infected cells was confirmed by in vitro experiments. Together, our findings uncovered a significant correlation of recovered Vδ2 with EBV reactivation following haploHSCT. These results will help to better understand the intrinsic anti-virus immunity and develop γδ T-based therapy strategies after haematopoietic transplantation.
Asunto(s)
Infecciones por Virus de Epstein-Barr/etiología , Genes Codificadores de la Cadena delta de los Receptores de Linfocito T , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4/fisiología , Linfocitos T/metabolismo , Activación Viral , Adolescente , Adulto , Apoptosis/genética , Apoptosis/inmunología , Citotoxicidad Inmunológica , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/genética , Antígenos HLA/inmunología , Haplotipos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Trasplante Homólogo , Adulto JovenRESUMEN
Emerging evidence from graft manipulations and immunotherapeutic treatments has highlighted a favorable effect of γδ T cells in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT). However, γδ T cell subsets and their distinct features in the allograft have not been characterized. Additionally, whether homeostatic γδ T cell fractions are influenced by treatment with granulocyte colony-stimulating factor (G-CSF) remains elusive. We initially compared the phenotypes of γδ T cell subsets, including CD27+, CD27-, Vδ1+, Vδ2+, Vδ1+CD27+, Vδ1+CD27-, Vδ2+CD27+, and Vδ2+CD27- cells, in the peripheral blood of 20 healthy donors before and after G-CSF mobilization. The effects of G-CSF on the cytokine production capacities of γδ T cell subsets were also detected. Moreover, the correlation between donor homeostatic γδ T cell content and the early recoveries of γδ T cell subgroups after haploidentical HSCT was investigated in 40 pairs of donors and recipients. We found that both the proportions and IFN-γ secretion capacities of peripheral γδ T cell subsets were preserved in G-CSF-primed grafts. Homeostatic Vδ1 and Vδ2 proportions of donors significantly correlated with the early recoveries of Vδ1 and Vδ2 cells after haploidentical HSCT. Interestingly, a higher day 30 Vδ1 concentration was associated with a lower incidence of cytomegalovirus reactivation in recipients. These results not only clarify the preservation of γδ T cell phenotypes and functional features by G-CSF mobilization but also suggest the importance of homeostatic γδ T cell content for immune recovery after alloHSCT.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Trasplante de Células Madre Hematopoyéticas/métodos , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Adolescente , Adulto , Femenino , Movilización de Célula Madre Hematopoyética , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función/efectos de los fármacos , Trasplante Haploidéntico , Adulto JovenRESUMEN
Although the outcome of patients with acute myeloid leukemia (AML) has improved by optimized chemotherapy regimens and bone marrow transplantation, leukemia relapse remains one of the most challenging problems during therapy. Sustained existence of AML blasts is a fundamental determinant for the development of leukemia and resistance to therapy. Recent evidences suggest that Meis1 is tightly associated with the self-renewal capacity of normal hematopoietic stem cells. Meis1 was also found to be essential for the development of mixed lineage leukemia (MLL)-rearranged leukemia. Whether Meis1 functions independently of MLL abnormality in the context of leukemia is unclear. Herein, we identified a distinct expression pattern of Meis1 in patients with newly diagnosed AML without MLL abnormality. High levels of Meis1 expression were found in 64 of 95 (67.4%) AML patients; whereas, 31 of 95 (32.6%) patients showed dramatically lower levels of Meis1, compared with the median level of Meis1 in healthy donors. The whole cohort and subgroup analyses further demonstrated that high Meis1 expression levels were associated with a resistance to conventional chemotherapy, compared with the group with low Meis1 levels (P = 0.014 and P = 0.029, respectively). In vitro knockdown experiments highlighted a role of Meis1 in regulating maintenance and survival of human AML cells. These results implicate that Meis1 functions as an important regulator during the progression of human AML and could be a prognostic factor independent of MLL abnormality.
Asunto(s)
Reordenamiento Génico/genética , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Adolescente , Adulto , Femenino , Humanos , Células K562 , Masculino , Persona de Mediana Edad , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Adulto JovenRESUMEN
Resistance to arsenic and/or all-trans retinoic acid (ATRA) is a challenging problem in the clinical management of acute promyelocytic leukemia (APL). Acquired genetic mutations in the PML moiety of the PML-RARA fusion gene are found in some patients with relapsed/refractory APL. Whether all of the identified point mutations play a role and have a similar function in the mechanisms of arsenic resistance remains unknown. Here we performed in vitro functional analyses and a retrospective analysis of APL patients to investigate the effect of PML-RARA mutations in mediating resistance to arsenic trioxide. Among the 5-point mutations in the PML part of PML-RARA identified in patients with relapsed APL, we found that A216V, S214L, and A216T mutations could attenuate the negative regulation of arsenic on PML-RARA, resulting in the retention of oncoproteins. In contrast, L217F and S220G mutations functioned weakly in this context. Furthermore, we demonstrated that either increasing the concentration of arsenic trioxide or combining it with ATRA could overcome the mutation-triggered arsenic resistance in vitro. In addition to presenting more evidence to reinforce the correlation of genetic mutations in PML-RARA with arsenic efficacy, we provide novel insight into the functional difference of acquired mutations of PML-RARA both in vitro and in the clinical setting. Our findings may help predict the prognosis and select more effective strategies during APL therapy.