Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Immunol Rev ; 271(1): 173-84, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27088914

RESUMO

Thymus transplants were never used to correct T-cell intrinsic deficiencies, as it is generally believed that thymocytes have short intrinsic lifespans. This notion is based on multiple thymus transplantation experiments, where it was shown that thymus-resident cells were rapidly replaced by progenitors migrating from the bone marrow (BM). This substitution occurs even when bone marrow precursors are unable to generate T cells, as in Rag1/2(-) or severe combined immunodeficiency (SCID)-deficient mice. In contrast, two groups reported that neonatal thymi transplanted into mice that cannot respond to IL-7 harbor populations with extensive capacity to self-renew, which maintain continuous thymocyte generation for several months after surgery. The consequences of this self-renewal capacity differed in these two laboratories. We found that these thymus transplants rapidly reconstitute the full diversity of peripheral T-cell repertoires 1 month after surgery, the earliest time point studied. Moreover, transplantation experiments performed across major histocompatibility barriers show that allogeneic-transplanted thymi are not rejected, and allogeneic cells do not induce graft-versus-host disease, both syngeneic and allogeneic transplants inducing rapid protection from infection. These results indicate a potential use of neonatal thymus transplants to correct T-cell intrinsic deficiencies. The other group observed that continuous thymocyte renewal from BM precursors was fundamental to prevent tumor development. In the absence of this input, thymocytes from the transplanted thymus generated tumors with all the characteristics of T-cell acute lymphoblastic leukemia (T-ALL). Moreover, they suggested that the absence of BM competition was responsible for the T-ALLs developing in X-linked severe combined immunodeficiency (SCID)-X1 patients, deficient in the expression of IL2-Rγc . These patients were treated with autologous CD34(+) cells transfected with virus vectors expressing γc in the absence of myeloablation. We here review the potential therapeutic impact of thymus transplantation and compare the results of these two laboratories aiming to find an answer to the 'Dr Jekill versus Mr. Hyde' status of thymus transplantation experiments.


Assuntos
Imunodeficiência Combinada Severa/terapia , Linfócitos T/fisiologia , Timócitos/fisiologia , Timo/imunologia , Adenosina/análogos & derivados , Adenosina/imunologia , Animais , Autorrenovação Celular , Seleção Clonal Mediada por Antígeno , Humanos , Tolerância Imunológica , Interleucina-7/imunologia , Camundongos , Camundongos SCID , Timócitos/transplante , Timo/transplante , Transplante Homólogo
2.
PLoS One ; 10(9): e0136123, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26355460

RESUMO

Preterm birth is associated with abnormal respiratory functions throughout life. The mechanisms underlying these long-term consequences are still unclear. Shortening of telomeres was associated with many conditions, such as chronic obstructive pulmonary disease. We aimed to search for an association between telomere length and lung function in adolescents born preterm. Lung function and telomere length were measured in 236 adolescents born preterm and 38 born full-term from the longitudinal EPIPAGE cohort. Associations between telomere length and spirometric indices were tested in univariate and multivariate models accounting for confounding factors in the study population. Airflows were significantly lower in adolescents born preterm than controls; forced expiratory volume in one second was 12% lower in the extremely preterm born group than controls (p<0.001). Lower birth weight, bronchopulmonary dysplasia and postnatal sepsis were significantly associated with lower airflow values. Gender was the only factor that was significantly associated with telomere length. Telomere length correlated with forced expiratory flow 25-75 in the extremely preterm adolescent group in univariate and multivariate analyses (p = 0.01 and p = 0.02, respectively). We evidenced an association between telomere length and abnormal airflow in a population of adolescents born extremely preterm. There was no evident association with perinatal events. This suggests other involved factors, such as a continuing airway oxidative stress leading to persistent inflammation and altered lung function, ultimately increasing susceptibility to chronic obstructive pulmonary disease.


Assuntos
Lactente Extremamente Prematuro/metabolismo , Pulmão/fisiologia , Saliva/metabolismo , Homeostase do Telômero , Adolescente , Adulto , Fatores de Confusão Epidemiológicos , Feminino , Idade Gestacional , Humanos , Masculino , Estudos Prospectivos , Testes de Função Respiratória
3.
J Exp Med ; 209(8): 1401-8, 2012 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-22778388

RESUMO

Thymus transplants can correct deficiencies of the thymus epithelium caused by the complete DiGeorge syndrome or FOXN1 mutations. However, thymus transplants were never used to correct T cell-intrinsic deficiencies because it is generally believed that thymocytes have short intrinsic lifespans. This notion is based on thymus transplantation experiments where it was shown that thymus-resident cells were rapidly replaced by progenitors originating in the bone marrow. In contrast, here we show that neonatal thymi transplanted into interleukin 7 receptor-deficient hosts harbor populations with extensive capacity to self-renew, and maintain continuous thymocyte generation and export. These thymus transplants reconstitute the full diversity of peripheral T cell repertoires one month after surgery, which is the earliest time point studied. Moreover, transplantation experiments performed across major histocompatibility barriers show that allogeneic transplanted thymi are not rejected, and allogeneic cells do not induce graft-versus-host disease; transplants induced partial or total protection to infection. These results challenge the current dogma that thymocytes cannot self-renew, and indicate a potential use of neonatal thymus transplants to correct T cell-intrinsic deficiencies. Finally, as found with mature T cells, they show that thymocyte survival is determined by the competition between incoming progenitors and resident cells.


Assuntos
Células da Medula Óssea/citologia , Timócitos/citologia , Timo/transplante , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/imunologia , Receptores de Interleucina-7/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timócitos/imunologia , Timócitos/metabolismo , Timo/imunologia , Timo/metabolismo , Transplante Homólogo
4.
Immunol Lett ; 140(1-2): 1-6, 2011 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-21704078

RESUMO

The TCR-αß/γδ CD8αα intraepithelial T lymphocytes (T-IEL) located in the gut mucosa of the small intestine are an abundant population believed to have a major role in ensuring the integrity of the gut wall. Here, we describe their unique characteristics and the controversies regarding the origin and differentiation of these T-IELs. We show how accumulated experimental evidence has finally arrived at a unifying concept, which demonstrates that these cells originate from early thymus precursors that have not yet undergone TCR rearrangement and TCR-αß/γδ commitment. These precursors colonize the gut lamina propria during the perinatal period and complete rearrangements and TCR-αß/γδ commitment while migrating to the epithelium. Therefore, the gut epithelium, which shares the same embryonic origin as the thymus epithelium, behaves as a primary lymphoid organ responsible for the differentiation of a major local T cell set.


Assuntos
Mucosa Intestinal/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Timo/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Rearranjo Gênico , Humanos , Sistema Imunitário/embriologia , Sistema Imunitário/crescimento & desenvolvimento , Mucosa Intestinal/embriologia , Mucosa Intestinal/imunologia , Tecido Linfoide/imunologia , Receptores de Antígenos de Linfócitos T/genética , Timo/embriologia , Timo/imunologia
5.
Nat Med ; 17(6): 700-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21552268

RESUMO

The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.


Assuntos
Processamento Alternativo/genética , Tumores do Estroma Gastrointestinal/genética , Receptor 3 Desencadeador da Citotoxicidade Natural/genética , Processamento Alternativo/fisiologia , Linhagem Celular Tumoral , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/fisiopatologia , Humanos , Interferon gama/fisiologia , Interleucina-12/fisiologia , Células Matadoras Naturais/fisiologia , Proteína 1 de Membrana Associada ao Lisossomo/fisiologia , Receptor 3 Desencadeador da Citotoxicidade Natural/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/fisiologia , Fator de Necrose Tumoral alfa/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...