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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.
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
3.
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
4.
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
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 753-757, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552932

RESUMO

OBJECTIVE: To investigate the effects of dihydroartemisinin (DHA) on the proliferation and apoptosis of human T-cell acute lymphoblastic leukemia (T-ALL) Jurkat cell. METHODS: The effects of DHA on the proliferation of Jurkat cells and the recovery of DHA-inhibited cell viability by N-acetyl-L-cysteine (NAC) were examined by CCK-8 assay. Flow cytometry was performed to analyze the cell apoptosis and generation of reactive oxygen species (ROS). Western-blot was used to detected protein expression of DNA damage-related genes, as well as apoptosis-associated genes, respectively. RESULTS: DHA inhibited the proliferation of Jurkat cells, and shows a concentration-dependent manner(r =0.936), and NAC could partially restore the activity of DHA on cell proliferation inhibition. With the increase of drug concentration, the apoptosis rate (r =0.946) and ROS accumulation was increased (r =0.965). Western blot showed that the protein expressions of DNA damage-related gene γ-H2AX and apoptosis-related genes p53, c-Caspase3, BAX and cPARP were significantly increased, and BCL-2 protein expression was decreased. CONCLUSION: DHA can induce ROS production in Jurkat cells, which can cause DNA damage, activate the P53 apoptotic pathway, and promote apoptosis of cells.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Apoptose , Artemisininas , Humanos , Células Jurkat , Estresse Oxidativo , Espécies Reativas de Oxigênio
6.
Eur J Immunol ; 50(9): 1374-1385, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32357256

RESUMO

BACKGROUND: Adoptive NK cell infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients. The aim of this study was to test the activity of clinical-grade membrane-bound IL-21/4-1BBL-expanded NK cell products against AML in vivo. METHODS: Fresh peripheral blood mononuclear cells (PBMCs) were incubated with equal numbers of irradiated membrane-bound IL-21/4-1BBL-expressing K562 cells for 2-3 weeks to induce clinical-grade NK cell expansion. RESULTS: Expansion for 2 and 3 weeks produced ∼4 and 8 × 109 NK cells from 2 × 107 PBMCs. The production of CD107a and TNF-α in NK cell products in response to AML cell lines and primary blasts was higher than that observed in resting NK cells. The 2-week expanded NK cell products were xenografted into immunodeficient mice with leukemia and were persistently found in the BM, spleen, liver, lung, and peripheral blood for at least 13 days; furthermore, these expanded products reduced the AML burden in vivo. Compared with matched AML patients with persistent or relapsed minimal residual disease (MRD+ ) who underwent regular consolidation therapy, MRD+ patients who underwent NK treatment had better overall survival and showed no major adverse events. CONCLUSIONS: Clinical-grade mbIL-21/4-1BBL-expanded NK cells exhibited antileukemic activity against AML in vitro and in vivo.


Assuntos
Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/terapia , Ligante 4-1BB/imunologia , Ligante 4-1BB/metabolismo , Adulto , Idoso , Animais , Feminino , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Células K562 , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 88-92, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027258

RESUMO

OBJECTIVE: To study the effects of dihydroartemisinin (DHA) on the proliferation and apoptosis of acute myeloid leukemia (AML) cells. METHODS: The effects of DHA on the proliferation of acute myeloid leukemia cells and the inhibitory effect of Z-VAD-FMK on the DHA-induced cell apoptosis were detected by CCK-8 assay. The expression level of cleaved-caspased 3 was detected by indirect immunofluorescence. Western blot was used to quantify the protein expression of PTEN, p-Akt, AKT, ß-actin, and the apoptosis-associated proteins, such as C-PARP, Cleaved-caspase3 and Caspase3 respectively. RESULTS: DHA induced the AML cell apoptosis with concentration-dependent manner (rKasumi-1=-0.959, rKG-1=-0.956). The DHA could induce the accumulation of cleaved-caspase 3 and C-PARP in AML cells, activate PTEN gene and inhibited Akt phosphorylation. Apoptosis inhibitor Z-VAD-FMK could partially restored the activity of DHA-inhibited cell proliferation. CONCLUSION: Dihydroartemisinin induces AML cell apoptosis by inhibition of PTEN/AKT pathway. Dihydroartemisinin is expected to be a safe and effective drug for treatment of acute myeloid leukemia.


Assuntos
Leucemia Mieloide Aguda , Apoptose , Artemisininas , Linhagem Celular Tumoral , Proliferação de Células , Humanos , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais
8.
Clin Infect Dis ; 70(7): 1429-1437, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-31067570

RESUMO

BACKGROUND: Human cytomegalovirus (HCMV) infection, especially persistent HCMV infection, is an important cause of morbidity and mortality after allogenic stem cell transplantation (allo-SCT). Antiviral agents remain the first-line therapy but are limited by side effects and acquired resistance. METHODS: We evaluated the safety and efficacy of donor-derived HCMV-specific cytotoxic T cells (CTLs) as a first-line therapy for HCMV infection after allo-SCT and investigated the underlying mechanisms. RESULTS: In humanized HCMV-infected mice, first-line therapy with CTLs effectively combated systemic HCMV infection by promoting the restoration of graft-derived endogenous HCMV-specific immunity in vivo. In a clinical trial, compared with the pair-matched, high-risk control cohort, first-line therapy with CTLs significantly reduced the rate of persistent (2.9% vs 20.0%, P = .018) and late (5.7% vs 20.0%, P = .01) HCMV infection and cumulative incidence of persistent HCMV infection (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.10-0.82; P = .02), lowered 1-year treatment-related mortality (HR, 0.15. 95% CI, 0.11-0.90. P = .03), and improved 1-year overall survival (HR, 6.35; 95% CI, 1.05-9.00; P = .04). Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance. CONCLUSIONS: We provide robust support for the benefits of CTLs combined with antiviral drugs as a first-line therapy for treating HCMV infection and suggest that adoptively infused CTLs may stimulate the recovery of endogenous HCMV-specific immunity. CLINICAL TRIALS REGISTRATION: NCT02985775.


Assuntos
Antivirais , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Animais , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Humanos , Camundongos , Transplante de Células-Tronco , Transplante Homólogo
10.
Blood Adv ; 3(24): 4312-4325, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31869417

RESUMO

The rate and extent of natural killer (NK)-cell education after hematopoietic cell transplantation correlates with leukemia control. To study the effect of donor and host HLA on NK-cell reconstitution, single killer-cell immunoglobulin-like receptor (KIR)+ NK cells (exhibiting KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor) were grouped into 4 groups based on the interaction between donor/host HLA and donor inhibitory KIR in 2 cohorts (n = 114 and n = 276, respectively). On days 90 to 180 after transplantation, the absolute number and responsiveness against K562 cells (CD107a or interferon-γ expression) of single-KIR+ NK cells were higher in pairs where donor and host HLA both expressed ligands for donor inhibitory KIRs than in pairs where 1 or both of the donor and recipient HLA lacked at least 1 KIR ligand. NK-cell responsiveness was tuned commensurate with the number of inhibitory receptors from the donor. When both donor and host expressed the 3 major KIR ligands (HLA-C1, HLA-C2, and HLA-Bw4), NK cells expressing 3 inhibitory receptors (KIR2DL1/2DL3/3DL1) reached the maximum responsiveness against K562 cells compared with those NK cells expressing only 1 or 2 inhibitory receptors. When donor and host HLA both expressed all ligands for donor inhibitory KIRs, patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) showed the lowest recurrence rate after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In conclusion, this study demonstrates that when both donors and hosts present all the KIR ligands for donor KIRs, reconstituted NK cells achieve better functional education and contribute to least relapse among patients. This observation study was registered at www.clinicaltrials.gov as #NCT02978274.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptores KIR/metabolismo , Adolescente , Adulto , Biomarcadores , Feminino , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Teste de Histocompatibilidade , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Recidiva , Doadores de Tecidos , Transplante Haploidêntico , Resultado do Tratamento , Adulto Jovem
11.
Clin Immunol ; 205: 49-56, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31112757

RESUMO

Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in graft-versus-host disease prophylaxis because of its inhibitory function on T cells and B cells. However, the effect of MMF on natural killer cell reconstitution after allogenic hematological transplantation is largely unknown. The present study examined the effects of different MMF administration durations after haploidentical allo-HSCT on NK cell reconstitution. Ninety patients were enrolled in this study and defined into two groups in term of MMF duration. We found that MMF patients in the long-term MMF group were associated with a poor reconstitution of NK cells and a significantly lower cytotoxicity from day 30 to day 180 post-transplantation. Especially, the long-term MMF group inhibits reconstitution of NKp30 NK subsets, which correlated with higher risk of EBV viremia. Multivariate analysis showed that a better reconstitution of NKp30 cells was associated with lower EBV viremia (HR0.957, p = .04). In vitro experiments demonstrated that the active metabolite of MMF, mycophenolic acid (MPA), inhibited the proliferation and cytotoxicity of NK cells from healthy donors or patients at day 30 post-transplantation. In summary, our findings demonstrated that long-term MMF administration delayed the quality and quantity of NK cells, especially NKp30 subpopulations, which was associated with decreased EBV viremia post allogeneic HSCT.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune/imunologia , Imunossupressores/administração & dosagem , Células Matadoras Naturais/imunologia , Ácido Micofenólico/administração & dosagem , Viremia/epidemiologia , Adolescente , Adulto , Duração da Terapia , Feminino , Herpesvirus Humano 4 , Humanos , Imunossupressores/uso terapêutico , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Síndromes Mielodisplásicas/terapia , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Modelos de Riscos Proporcionais , Transplante Homólogo , Adulto Jovem
12.
Biol Blood Marrow Transplant ; 25(1): 1-11, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30142416

RESUMO

The immune mechanism underlying graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (HSCT) remains unclear. Natural killer (NK) cells play a crucial role in mediating pathogen-specific immunity and are the first donor-derived lymphocytes reconstituted post-HSCT. However, NK cells vary at different stages after HSCT. Here, we found that the absolute NKG2A+ subset cell counts and the percentages of NKG2A+ among NK cells were significantly reduced in GVHD patients after HSCT compared with those from non-GVHD patients. Moreover, the reduction in NKG2A+ NK cells in post-HSCT GVHD patients was ascribed to increased apoptosis and a decreased proliferation capacity while retaining a strong graft-versus-leukemia effect. In vitro assays showed that co-culture of T cells with NKG2A+ NK cells significantly reduced IFN-γ secretion by T cells and increased IL-4 secretion. Moreover, the CD25 expression level was decreased, whereas the number of cells with the CD4+CD25+FOXP3+ phenotype was increased. In addition, the NKG2A+ NK cells induced T cell apoptosis and decreased T cell proliferation during the co-culture process. Importantly, NKG2A+ NK cells mainly regulated activated but not resting T cells. In vivo assays showed that the serologic IL-10 level was evidently lower in GVHD than in non-GVHD patients, whereas the IL-1ß, IFN-γ, and tumor necrosis factor-α levels were higher in GVHD patients. Furthermore, the NKG2A+ NK cell ratio from GVHD patients was markedly increased by the presence of exogenous IL-10 but not by other cytokines. In contrast, the NKG2A+ cell ratio from non-GVHD patients was not increased by IL-10. Therefore, post-HSCT GVHD may be ascribed to the reduced induction of NKG2A+ NK cells by IL-10, which further overactivates T cells.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais , Leucemia , Síndromes Mielodisplásicas , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Adolescente , Adulto , Células Cultivadas , Criança , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Efeito Enxerto vs Leucemia/imunologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leucemia/imunologia , Leucemia/patologia , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Transplante Homólogo
13.
J Cell Mol Med ; 22(6): 3025-3034, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29575692

RESUMO

Granulocyte colony-stimulating factor (G-CSF) has been widely used in the field of allogeneic haematopoietic stem cell transplantation (allo-HSCT) for priming donor stem cells from the bone marrow (BM) to peripheral blood (PB) to collect stem cells more conveniently. Donor-derived natural killer (NK) cells have important antitumour functions and immune regulatory roles post-allo-HSCT. The aim of this study was to evaluate the effect of G-CSF on donors' NK cells in BM and PB. The percentage of NK cells among nuclear cells and lymphocyte was significantly decreased and led to increased ratio of T and NK cells in BM and PB post-G-CSF in vivo application. Relative expansion of CD56bri NK cells led to a decreased ratio of CD56dim and CD56bri NK subsets in BM and PB post-G-CSF in vivo application. The expression of CD62L, CD54, CD94, NKP30 and CXCR4 on NK cells was significantly increased in PB after G-CSF treatment. G-CSF treatment decreased the IFN-γ-secreting NK population (NK1) dramatically in BM and PB, but increased the IL-13-secreting NK (NK2), TGF-ß-secreting NK (NK3) and IL-10-secreting NK (NKr) populations significantly in BM. Clinical data demonstrated that higher doses of NK1 infused into the allograft correlated with an increased incidence of chronic graft-vs-host disease post-transplantation. Taken together, our results show that the in vivo application of G-CSF can modulate NK subpopulations, leading to an increased ratio of T and NK cells and decreased ratio of CD56dim and CD56bri NK cells as well as decreased NK1 populations in both PB and BM.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Doença Enxerto-Hospedeiro/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Adolescente , Adulto , Transplante de Medula Óssea/métodos , Antígeno CD56/genética , Criança , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Fator Estimulador de Colônias de Granulócitos/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Molécula 1 de Adesão Intercelular/genética , Interferon gama/genética , Interleucina-13/genética , Células Matadoras Naturais/transplante , Selectina L/genética , Masculino , Pessoa de Meia-Idade , Subfamília D de Receptores Semelhantes a Lectina de Células NK/genética , Receptor 3 Desencadeador da Citotoxicidade Natural/genética , Receptores CXCR4/genética , Transplante Homólogo/métodos , Adulto Jovem
14.
Transpl Immunol ; 48: 55-59, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29475092

RESUMO

INTRODUCTION: Invariant natural killer T cells (iNKTs) are a rare but vital subset of immunomodulatory T cells and play an important role in allogeneic hematopoietic stem cell trans-plantation (HSCT). The association of donor characteristics with the number and frequency of the iNKTs subsets in allografts remains poorly understood. In this paper, we prospectively investigate the association of donor characteristics with iNKTs dose and frequency in granulocyte-colony-stimulating factor (G-CSF) mobilized marrow and peripheral blood harvests. MATERIALS AND METHODS: 100 bone marrow (BM) units and 100 peripheral blood (PB) units from 100 healthy donors were examined. Parameters including donor age, sex, weight, height, BMI and blood count [including white blood cells (WBCs), lymphocytes and monocytes] at three time points [donor's steady state before G-CSF administration, the day of G-BM harvesting and the day of G-PB apheresis] were analyzed to explore the impact of donor characteristics on iNKTs composition in BM and PB grafts. RESULTS: Multivariate analysis showed monocyte counts before G-BM harvest could predict higher frequency of iNKTs in WBC (OR = 2.593, 95%CI: 1.128-5.961, p = 0.025), higher total CD4+ iNKTs dose (OR = 2.250, 95%CI: 1.011-5.008, p = 0.047) and higher total iNKTs dose (OR = 2.662, 95%CI: 1.187-5.970, p = 0.017) in mixture allografts. DISCUSSION: The results suggested that monocyte counts pre G-BM harvest could predict the yield of total CD4+ iNKTs and total iNKTs in mixture allografts. The male and older donors were associated with a higher dose of total CD4- iNKTs in mixture allografts.


Assuntos
Medula Óssea/imunologia , Transplante de Células-Tronco Hematopoéticas , Células T Matadoras Naturais/imunologia , Doadores de Tecidos , Adolescente , Adulto , Idoso , Transfusão de Sangue , Medula Óssea/patologia , Antígenos CD4/metabolismo , Criança , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Humanos , Imunomodulação , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo , Adulto Jovem
15.
Br J Haematol ; 177(5): 766-781, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28466469

RESUMO

Licensed natural killer (NK) cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor-recipient pairs and the killer cell immunoglobulin-like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post-T-cell-replete haploidentical stem cell transplantation. Multivariate analysis showed that donor-recipient KIR ligand graft-versus-host or host-versus-graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377-4·744, P = 0·003) post-transplantation. Donor-recipient KIR ligand matching decreased CMV reactivation [51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012], refractory CMV infection [17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004] and CMV disease [3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024] by day 100 post-transplantation. In addition, the percentage of γ-interferon expression on donor-derived NK cells was significantly higher in the recipients among the recipient-donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft-versus-host or host-versus-graft direction mismatch on days 30 and 100 post-transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor-recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell-mediated protection against CMV reactivation.


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Linfócitos T/transplante , Adolescente , Adulto , Criança , Citomegalovirus/fisiologia , Feminino , Neoplasias Hematológicas/terapia , Teste de Histocompatibilidade/métodos , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores KIR/genética , Receptores KIR/imunologia , Transplante de Células-Tronco/métodos , Transplantados , Condicionamento Pré-Transplante/métodos , Ativação Viral/genética , Ativação Viral/imunologia , Adulto Jovem
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