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1.
Biomedicines ; 10(10)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36289926

RESUMO

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with an unknown etiology, although genetic, epigenetic, and environmental factors are thought to play a role. Recently, coagulation components have been shown to provide immunomodulatory and pro-inflammatory effects in the CNS, leading to neuroinflammation and neurodegeneration. The current study aimed to determine whether patients with MS exhibited an overrepresentation of polymorphisms implicated in the coagulation and whether such polymorphisms are associated with advanced disability and disease progression. The cardiovascular disease (CVD) strip assay was applied to 48 MS patients and 25 controls to analyze 11 genetic polymorphisms associated with thrombosis and CVD. According to our results, FXIIIVal34Leu heterozygosity was less frequent (OR: 0.35 (95% CI: 0.12-0.99); p = 0.04), whereas PAI-1 5G/5G homozygosity was more frequent in MS (OR: 6.33 (95% CI: 1.32-30.24); p = 0.016). In addition, carriers of the HPA-1a/1b were likely to have advanced disability (OR: 1.47 (95% CI: 1.03-2.18); p = 0.03) and disease worsening (OR: 1.42 (95% CI: 1.05-2.01); p = 0.02). The results of a sex-based analysis revealed that male HPA-1a/1b carriers were associated with advanced disability (OR: 3.04 (95% CI: 1.22-19.54); p = 0.01), whereas female carriers had an increased likelihood of disease worsening (OR: 1.56 (95% CI: 1.04-2.61); p = 0.03). Our findings suggest that MS may be linked to thrombophilia-related polymorphisms, which warrants further investigation.

2.
Br J Haematol ; 194(1): 158-167, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34036576

RESUMO

Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Sangue Fetal/citologia , Imunoterapia Adotiva/métodos , Leucemia/terapia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Proteínas WT1/imunologia , Antígenos CD/análise , Bancos de Sangue/economia , Diferenciação Celular , Células Cultivadas , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Citotoxicidade Imunológica , Células Dendríticas/citologia , Células Dendríticas/transplante , Humanos , Separação Imunomagnética , Imunofenotipagem , Imunoterapia Adotiva/economia , Leucemia/economia , Células T de Memória/imunologia , Células T de Memória/transplante , Subpopulações de Linfócitos T/transplante , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/transplante
3.
Hum Immunol ; 65(2): 135-41, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14969768

RESUMO

Cytokines are critical immunoregulatory molecules, responsible for determining the nature of an immune response. It has been proposed that Th2/Th3 immune reactions support normal pregnancy, while Th1 immunity is considered detrimental to the fetus. Since cytokine production is partly under genetic control, it is possible that women suffering from a high incidence of abortions are genetically predisposed to mount a type of immune response inappropriate for pregnancy maintenance. This study investigated the frequencies of cytokine gene polymorphisms in abortion-prone women and women with successful pregnancies. We investigated the role of Th1/Th2/Th3 cytokine gene polymorphisms, such as TGF-beta1 codon 10 (TGFbetac10; C to T), TGF-beta1 codon 25 (TGFbetac25; G to C), TNFalpha promoter-308 (G to A), IL-6 promoter-174 (G to C), IL-10 promoter-1082 (G to A), IL-10 promoter-819 (C to T), IL-10 promoter-592 (C to A), and IFNgamma intron 1 +874 (A to T) in abortion-prone female patients. Our results support the importance of Th2/Th3 immune responses in pregnancy loss, and suggest that an individual's immunogenetic profile indicative of imbalances in Th2/Th3 cytokines is associated with pregnancy loss. Our results suggest that abortive events are determined by genetic factors, reflected in the female patient's immunogenetic profile.


Assuntos
Aborto Espontâneo/genética , Citocinas/genética , Linfócitos T Auxiliares-Indutores/imunologia , Células Th2/imunologia , Aborto Espontâneo/imunologia , Citocinas/imunologia , Interpretação Estatística de Dados , Perda do Embrião/genética , Perda do Embrião/imunologia , Feminino , Frequência do Gene , Genótipo , Número de Gestações/genética , Número de Gestações/imunologia , Haplótipos/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Paridade/genética , Paridade/imunologia , Polimorfismo Genético , Gravidez , Regiões Promotoras Genéticas/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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