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1.
Front Immunol ; 13: 814334, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572602

RESUMO

NKG2C+ natural killer (NK) cell plays a vital role in CMV infection control after hematopoietic stem cell transplantation (HSCT). However, the modulation on NKG2C+ NK cell reconstitution is still unclear. NK cell education is affected by the interactions of HLA-I/killer immunoglobulin receptor (KIR). Our aim is to figure out which HLA-I/KIR interaction plays a dominant role in NKG2C+ NK education. Based on allogeneic haploidentical HSCT, we investigated the expansion and function of single KIR positive NKG2C+ NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after HSCT. KIR2DL2/L3 single-positive/NKG2C+ cells were significantly expanded compared with KIR2DL1 or KIR3DL1 single-positive/NKG2C+ cells when donors and recipients were both HLA-C1/C1 or HLA-C1C1BW4 (p < 0.05), with higher NKp30 expression (p < 0.05). Moreover, the proportion of single KIR positive NK cells increased in both NKG2C+/NKG2A- NK cells and conventional NKG2C-/NKG2A- NK cells over time. We also observed that increased proportion of KIR2DL2/L3 single-positive/NKG2C+ NK cells correlated with higher incidence of acute graft-versus-host disease (aGVHD). Our study allows a better understanding of HLA-I/KIR interaction in the NKG2C+ NK cell education after HSCT.

2.
Clin Exp Immunol ; 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35551362

RESUMO

Cytomegalovirus (CMV) infection and acute graft-versus-host disease (aGVHD) are two major complications that contribute to a poor prognosis after hematopoietic stem cell transplantation (HSCT). Superior early immune reconstitution (IR) is associated with improved survival after HSCT. However, when all three factors, CMV infection, aGVHD, and IR, are concomitantly considered, the effects of the triple events on HSCT are still unknown and should be studied further. Thus we enrolled 185 patients who were diagnosed as hematological malignancies and treated with HLA-matched sibling transplantation (MST) between January 2010 and December 2014, of whom 83 were positive for CMV infection and 82 had aGVHD. Results showed that patients with both aGVHD and CMV infection had significantly higher non-relapse mortality (NRM), lower overall survival (OS), and delayed CD8+ T-cell IR. Multivariate analyses showed that both aGVHD combined with CMV infection and delayed CD8+ T-cell IR were independent risk factors for post-MST prognosis. Recurrent CMV infections are associated with poor CD8+ T-cell reconstitution. However, superior IR could protect against the negative effects of aGVHD and CMV infection on the transplant outcomes.

3.
Int J Biol Sci ; 18(5): 1974-1988, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35342342

RESUMO

CD38 is highly expressed on multiple myeloma (MM) cells and plays a role in regulating tumor generation and development. CD38 monoclonal antibodies (mAbs) have been used as an effective therapy for MM treatment by various mechanisms, including complement-dependent cytotoxic effects, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, enzymatic modulation, and immunomodulation. Although CD38 mAbs inhibit the proliferation and survival of MM cells, there are substantial side effects on antitumoral NK cells. The NK-mediated immune response needs to be further evaluated to minimize the adverse effects of NK cell loss. The killing effect of CD38 mAbs on CD38high NK cells should be minimized and the potential combination of CD38low/- NK cells and CD38 mAbs should be maximized to better benefit from their therapeutic efficacy against MM. CD38 mAb effects against MM can be maximized by combination therapies with immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs), anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies, or cellular therapies for the treatment of MM, especially in patients with relapsed or refractory MM (R/R MM) and drug-resistant MM.


Assuntos
Mieloma Múltiplo , ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase 1/farmacologia , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Humanos , Células Matadoras Naturais , Mieloma Múltiplo/tratamento farmacológico
4.
Am J Hematol ; 97(6): 762-769, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35293011

RESUMO

Adoptive therapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50% to 90%, and factors affecting anti-CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV-CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo-SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0-503.0) × 103 copies/mL to 3.9 (range, 0-112) × 103 copies/mL after CMV-CTL infusion. The cumulative complete response (CR) rates in the first, fourth, and sixth weeks after the first CMV-CTL infusion were 37.9% (95% CI 35.0-40.8), 76.8% (95% CI 70.7-82.9), and 89.5% (95% CI 85.2-93.8), respectively. In multivariate analysis, persistent CMV infection prior to CMV-CTL infusion (hazard ratio [HR] 2.29, 95% CI 1.29-4.06, p = .005) and basiliximab treatment within 2 weeks of CMV-CTL infusion (HR 1.87, 95% CI 1.06-3.81, p = .031) were independent predictors of poor antiviral efficacy of CMV-CTL therapy. Our data showed that adoptive therapy with CMV-CTLs is a safe and effective treatment for CMV infection after haplo-SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti-CMV efficacy of CMV-CTL therapy.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Antivirais/uso terapêutico , Basiliximab/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplante de Células-Tronco , Linfócitos T Citotóxicos
5.
Cell Mol Immunol ; 19(4): 482-491, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35017718

RESUMO

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Animais , Citomegalovirus , Humanos , Camundongos , Transplante de Células-Tronco , Linfócitos T Citotóxicos , Doadores de Tecidos
6.
JCI Insight ; 7(3)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-34990406

RESUMO

CMV infection remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several investigators have reported that adaptive NKG2C+ NK cells persistently expand during CMV reactivation. In our study, 2 cohorts were enrolled to explore the relationships among the NKG2C genotype, NKG2C+ NK cell reconstitution, and CMV infection. Multivariate analysis showed that donor NKG2C gene deletion was an independent prognostic factor for CMV reactivation and refractory CMV reactivation. Furthermore, adaptive NKG2C+ NK cells' quantitative and qualitative reconstitution, along with their anti-CMV function after transplantation, was significantly lower in patients grafted with NKG2Cwt/del donor cells than in those grafted with NKG2Cwt/wt donor cells. At day 30 after transplantation, quantitative reconstitution of NKG2C+ NK cells was significantly lower in patients with treatment-refractory CMV reactivation than in patients without CMV reactivation and those with nonrefractory CMV reactivation. In humanized CMV-infected mice, we found that, compared with those from NKG2Cwt/del donors, adaptive NKG2C+ NK cells from NKG2Cwt/wt donors induced earlier and stronger expansion of NKG2C+ NK cells as well as earlier and stronger CMV clearance in vivo. In conclusion, donor NKG2C homozygosity contributes to CMV clearance by promoting the quantitative and qualitative reconstruction of adaptive NKG2C+ NK cells after haploidentical allo-HSCT.


Assuntos
Infecções por Citomegalovirus/genética , Rejeição de Enxerto/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células Matadoras Naturais/patologia , Mutação , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Doadores de Tecidos , Adolescente , Adulto , Animais , Linhagem Celular , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , DNA/genética , Análise Mutacional de DNA , Feminino , Seguimentos , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Homozigoto , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Masculino , Camundongos , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Estudos Prospectivos , Transplante Haploidêntico , Ativação Viral , Adulto Jovem
7.
Br J Haematol ; 196(4): 1007-1017, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34787307

RESUMO

Natural killer (NK) cells exert anti-viral effects after haematopoietic stem cell transplantation (HSCT). The balance between inhibition and activation of NK cells determined by the inherited repertoire of killer cell immunoglobulin-like receptors (KIR) genes may influence Epstein-Barr virus (EBV) reactivation after transplantation. To evaluate the relative contributions of KIR genotypes to EBV reactivation, we prospectively enrolled 300 patients with malignant haematological disease who were suitable for haploidentical HSCT. Univariate analysis showed that donors with KIR2DS1, KIR2DS3 or KIR3DS1 genes were associated with an increased risk of EBV reactivation [hazard ratio (HR) 1·86, 95% confidence interval (CI) 1·19-2·9, P = 0·0067; HR 1·78, 95% CI 1·07-2·97, P = 0·027; HR 1·86, 95% CI 1·19-2·91, P = 0·0065 respectively]. Multivariate analysis revealed that the presence of KIR2DS1, KIR2DS3 or KIR3DS1 genes was associated with increased EBV reactivation after HSCT. This effect was more evident in the absence of the cognate ligands for the corresponding activating receptors. Our present data firstly showed that donors with activating KIR genes, specifically activating KIR2DS1, KIR2DS3 and KIR3DS1, had an increased risk of EBV reactivation. Precaution for patients whose donors carry activating genes will help prevent EBV reactivation and improve patient prognosis after HSCT.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Receptores KIR/genética , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
J Immunol ; 208(2): 492-500, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34937746

RESUMO

The interaction of inhibitory receptors with self-MHC class I (MHC-I) molecules is responsible for NK cell education. The intensity of DNAM-1 expression correlates with NK cell education. However, whether DNAM-1 expression directly influences the functional competence of NK cells via the KIR/MHC-I interaction remains unclear. Based on allogeneic haploidentical hematopoietic stem cell transplantation, we investigated the intensity of DNAM-1 expression on reconstituted NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after hematopoietic stem cell transplantation. The reconstituted NK cells educated by donor and recipient HLA molecules showed the highest DNAM-1 expression, whereas DNAM-1 expression on educated NK cells with only recipient HLA molecules was higher than that on educated NK cells with only donor HLA molecules, indicating that NK cells with donor or recipient HLA molecules regulate DNAM-1 expression and thereby affect NK cell education. Additionally, the effects of recipient cells on NK cell education were greater than those of donor cells. However, only when the DNAM-1, NKP30, and NKG2D receptors were blocked simultaneously was the function of educated and uneducated NK cells similar. Therefore, activating receptors may collaborate with DNAM-1 to induce educated NK cell hyperresponsiveness. Our data, based on in vitro and in vivo studies, demonstrate that the functional competence of NK cells via the KIR/MHC-I interaction correlates with DNAM-1 expression in human NK cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Estudos de Casos e Controles , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Linfoide/terapia , Leucemia Mieloide/terapia , Síndromes Mielodisplásicas/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Estudos Prospectivos
10.
Front Oncol ; 11: 758512, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778077

RESUMO

Haploidentical stem cell transplantation (haplo-SCT), an alternative donor source, offers a curative therapy for patients with acute myeloid leukemia (AML) who are transplant candidates. Advances in transplantation techniques, such as donor selection, conditioning regimen modification, and graft-versus-host disease prophylaxis, have successfully improved the outcomes of AML patients receiving haplo-SCT and extended the haploidentical transplant indictions for AML. Presently, treating de novo AML, secondary AML, therapy-related AML and refractory and relapsed AML with haplo-SCT can achieve comparable outcomes to those of human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT), unrelated donor transplantation or umbilical cord blood transplantation. For some subgroups of AML subjects, such as patients with positive pretransplantation minimal/measurable residual disease, recent studies suggest that haplo-SCT might be superior to MSDT in decreasing relapse and improving survival. Unfortunately, for patients with AML after haplo-SCT, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes. In this review, we discuss the recent advances and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haplo-SCT protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.

11.
Front Plant Sci ; 12: 738261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630489

RESUMO

Maize is one of the major crops in the world; however, diseases caused by various pathogens seriously affect its yield and quality. The maize Rp1-D21 mutant (mt) caused by the intragenic recombination between two nucleotide-binding, leucine-rich repeat (NLR) proteins, exhibits autoactive hypersensitive response (HR). In this study, we integrated transcriptomic and metabolomic analyses to identify differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) in Rp1-D21 mt compared to the wild type (WT). Genes involved in pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) were enriched among the DEGs. The salicylic acid (SA) pathway and the phenylpropanoid biosynthesis pathway were induced at both the transcriptional and metabolic levels. The DAMs identified included lipids, flavones, and phenolic acids, including 2,5-DHBA O-hexoside, the production of which is catalyzed by uridinediphosphate (UDP)-dependent glycosyltransferase (UGT). Four maize UGTs (ZmUGTs) homologous genes were among the DEGs. Functional analysis by transient co-expression in Nicotiana benthamiana showed that ZmUGT9250 and ZmUGT5174, but not ZmUGT9256 and ZmUGT8707, partially suppressed the HR triggered by Rp1-D21 or its N-terminal coiled-coil signaling domain (CCD21). None of the four ZmUGTs interacted physically with CCD21 in yeast two-hybrid or co-immunoprecipitation assays. We discuss the possibility that ZmUGTs might be involved in defense response by regulating SA homeostasis.

12.
Front Immunol ; 12: 720354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539656

RESUMO

Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosa-associated invariant T (MAIT) cells are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT cells in the occurrence of gut aGVHD in humans. In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyze the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAIT cells. The number and distribution of MAIT cells in intestinal tissues were analyzed by immunofluorescence technology. Our study showed that the number and frequency of MAIT cells in infused grafts in gut aGVHD patients were lower than those in no-gut aGVHD patients. Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early posttransplantation period (+14 days). At the onset of gut aGVHD, the number of MAIT cells decreased in peripheral blood, and the activation marker CD69, chemokine receptors CXCR3 and CXCR4, and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAIT cells secreted more granzyme B, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ under the interleukin (IL)-12/IL-18 stimulation [non-T-cell receptor (TCR) signal] and secreted most of the IL-17 under the cluster of differentiation (CD)3/CD28 stimulation (TCR signal). MAIT cells inhibited the proliferation of CD4+ T cells in vitro. In conclusion, the lower number of MAIT cells in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAIT cells in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAIT cells and promoted the expression of intestinal protective factors to affect the occurrence of gut aGVHD in humans.


Assuntos
Suscetibilidade a Doenças , Gastroenteropatias/etiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Adolescente , Adulto , Biomarcadores , Citocinas/metabolismo , Disbiose , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunomodulação , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transdução de Sinais , Transplante Homólogo/efeitos adversos , Adulto Jovem
13.
Blood Adv ; 5(24): 5479-5489, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34507352

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempted to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort, according to the time of transplantation, to perform external temporal validation. Patient age (odds ratio [OR], 2.371; 95% confidence interval [CI], 1.264-4.445), anemia (OR, 2.836; 95% CI, 1.566-5.138), severe thrombocytopenia (OR, 3.871; 95% CI, 2.156-6.950), elevated total bilirubin (OR, 2.716; 95% CI, 1.489-4.955), and proteinuria (OR, 2.289; 95% CI, 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was constructed according to the regression coefficients. The validated c-statistic was 0.816 (95%, CI, 0.766-0.867) and 0.756 (95% CI, 0.696-0.817) for the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia
14.
Bone Marrow Transplant ; 56(11): 2723-2731, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34239051

RESUMO

The objective of this study was to compare clinical outcomes between noninherited maternal antigen (NIMA)-mismatched and noninherited paternal antigen (NIPA)-mismatched haploidentical hematopoietic stem cell transplantation (haplo-HSCT) among patients with hematological malignancies and perform a subgroup analysis. We retrospectively analyzed 378 patients with hematological malignancies who received haplo-HSCT from NIMA-mismatched (n = 201) and NIPA-mismatched (n = 177) donors between January 2012 and December 2017. The cumulative incidence of 100-d grades II-IV acute graft-versus-host disease (aGVHD) (19.2% vs. 32.8%, P = 0.003) was significantly lower in NIMA mismatch. Multivariate analysis showed that NIMA mismatch was associated with lower incidence of grades II-IV aGVHD and better overall survival (OS) and disease-free survival (DFS). According to the subgroup analysis, the clinical outcomes of older and/or female NIMA mismatches were comparable to those of younger and/or male NIPA mismatches with respect to grades II-IV aGVHD, chronic GVHD (cGVHD), nonrelapse mortality (NRM), relapse, DFS, and OS. In conclusion, this study confirmed the NIMA effect on aGVHD and demonstrated that NIMA mismatch was associated with better survival. In the NIMA mismatch context, donor age and sex did not seem to influence haplo-HSCT, which provides a basis for the selection of sibling donors.


Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Recidiva Local de Neoplasia , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos
15.
Plant Sci ; 308: 110901, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34034862

RESUMO

Nitrogen is an essential macronutrient for plants and regulates many aspects of plant growth and development. Nitrate is one of the major forms of nitrogen in plants. However, the role of nitrate uptake and allocation in seed development is not fully understood. Here, we identified the maize (Zea mays) small-kernel mutant zmnpf7.9 and characterized the candidate gene, ZmNPF7.9, which was the same gene as nitrate transport 1.5 (NRT1.5) in maize. This gene is specifically expressed in the basal endosperm transfer layer cells of maize endosperm. Dysfunction of ZmNPF7.9 resulted in delayed endosperm development, abnormal starch deposition and decreased hundred-grain weight. Functional analysis of cRNA-injected Xenopus oocytes showed that ZmNPF7.9 is a low-affinity, pH-dependent bidirectional nitrate transporter. Moreover, the amount of nitrate in mature seeds of the zmnpf7.9 mutant was reduced. These suggest that ZmNPF7.9 is involved in delivering nitrate from maternal tissues to the developing endosperm. Moreover, most of the key genes associated with glycolysis/gluconeogenesis, carbon fixation, carbon metabolism and biosynthesis of amino acids pathways in the zmnpf7.9 mutant were significantly down-regulated. Thus, our results demonstrate that ZmNPF7.9 plays a specific role in seed development and grain weight by regulating nutrition transport and metabolism, which might provide useful information for maize genetic improvement.


Assuntos
Proteínas de Transporte de Ânions/genética , Proteínas de Plantas/genética , Sementes/crescimento & desenvolvimento , Zea mays/crescimento & desenvolvimento , Zea mays/genética , Proteínas de Transporte de Ânions/metabolismo , Endosperma/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Amido/metabolismo , Zea mays/metabolismo
16.
Leukemia ; 35(11): 3092-3100, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33824464

RESUMO

Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P = 0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/efeitos adversos , Recidiva Local de Neoplasia/terapia , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Terapia de Salvação , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Haploidêntico
17.
Front Immunol ; 12: 610789, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815365

RESUMO

Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras-MEK-MAPK, JAK-STAT5, and PI3K-ATK-mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.


Assuntos
Diferenciação Celular , Interleucina-15/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Fatores de Transcrição/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interleucina-15/genética , Células Matadoras Naturais/imunologia , Linfopoese/genética , Linfopoese/imunologia , Transdução de Sinais , Fatores de Transcrição/genética
18.
J Integr Plant Biol ; 63(1): 228-243, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32437079

RESUMO

Plant cells have a powerful capacity in their propagation to adapt to environmental change, given that a single plant cell can give rise to a whole plant via somatic embryogenesis without the need for fertilization. The reprogramming of somatic cells into totipotent cells is a critical step in somatic embryogenesis. This process can be induced by stimuli such as plant hormones, transcriptional regulators and stress. Here, we review current knowledge on how the identity of totipotent cells is determined and the stimuli required for reprogramming of somatic cells into totipotent cells. We highlight key molecular regulators and associated networks that control cell fate transition from somatic to totipotent cells. Finally, we pose several outstanding questions that should be addressed to enhance our understanding of the mechanisms underlying plant cell totipotency.


Assuntos
Reprogramação Celular/fisiologia , Células Vegetais/metabolismo , Reprogramação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Técnicas de Embriogênese Somática de Plantas
19.
Plant Cell Environ ; 44(1): 88-101, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32677712

RESUMO

Germination is a plant developmental process by which radicle of mature seeds start to penetrate surrounding barriers for seedling establishment and multiple environmental factors have been shown to affect it. Little is known how high salinity affects seed germination of C4 plant, Zea mays. Preliminary germination assay suggested that isolated embryo alone was able to germinate under 200 mM NaCl treatment, whereas the intact seeds were highly repressed. We hypothesized that maize endosperm may function in perception and transduction of salt signal to surrounding tissues such as embryo, showing a completely different response to that in Arabidopsis. Since salt response involves ABA, we analysed in vivo ABA distribution and quantity and the result demonstrated that ABA level in isolated embryo under NaCl treatment failed to increase in comparison with the water control, suggesting that the elevation of ABA level is an endosperm dependent process. Subsequently, by using advanced profiling techniques such as RNA sequencing and SWATH-MS-based quantitative proteomics, we found substantial differences in post-transcriptional and translational changes between salt-treated embryo and endosperm. In summary, our results indicate that these regulatory mechanisms, such as alternative splicing, are likely to mediate early responses to salt stress during maize seed germination.


Assuntos
Sementes/metabolismo , Cloreto de Sódio/metabolismo , Zea mays/genética , Ácido Abscísico/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Giberelinas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Proteoma , Estresse Salino , Sementes/crescimento & desenvolvimento , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo
20.
Front Immunol ; 12: 731435, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35069522

RESUMO

Background: The presence of minimal residual disease (MRD) is an independent risk factor for poor prognosis in patients with acute lymphoblastic leukemia (ALL). Moreover, the role of chimeric antigen receptor T-cell (CAR-T) therapy in patients with MRD is currently unclear. Methods: We conducted a prospective study to investigate the role of CAR-T therapy in patients with persistent/recurrent MRD-positive ALL in first remission. Results: A total of 77 patients who had persistent/recurrent MRD were included. Of these patients, 43 were enrolled in the CAR-T group, 20 received chemotherapy as a bridge to allogeneic hematopoietic cell transplantation (allo-HSCT), and 14 patients received intensified chemotherapy. MRD negativity was achieved in 90.7% of the patients after CAR-T infusion. Patients who received CAR-T therapy had a higher 3-year leukemia-free survival (LFS) than patients who did not (77.8% vs. 51.1%, P = 0.033). Furthermore, patients in the CAR-T group had a higher 3-year LFS than those in the chemotherapy bridge-to-allo-HSCT group [77.8% (95% CI, 64.8-90.7%) vs. 68.7% (95% CI, 47.7-89.6%), P = 0.575] and had a significantly higher 3-year LFS than those in the intensified chemotherapy group [77.8% (95% CI, 64.8-90.7%) vs. 28.6% (95% CI, 4.9-52.3%), P = 0.001]. Among the patients who received CAR-T therapy, eight were not bridged to allo-HSCT, and six (75%) remained in remission with a median follow-up of 23.0 months after CAR-T infusion. Conclusions: Our findings show that CAR-T therapy can effectively eliminate MRD and improve survival in patients with a suboptimal MRD response.


Assuntos
Transferência Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Prospectivos , Indução de Remissão , Taxa de Sobrevida
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