Leukotriene B4 mediates γδ T lymphocyte migration in response to diverse stimuli

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141926/1/jlb0323.pd

Avaliação de ensaios clínicos no Brasil: histórico e atualidades

Resumo Ensaios clínicos devem ser aprovados e acompanhados por autoridades éticas e regulatórias para garantir que a conduta ética e os aspectos técnicos das pesquisas estejam em conformidade com os padrões exigidos. O conhecimento desse processo é primordial para que estudos sejam delineados e conduzidos de acordo com os padrões aplicáveis, sendo parte essencial para a capacitação técnica e científica nacional. No Brasil, a avaliação dos estudos é realizada pelos comitês de ética em pesquisa, pela Comissão Nacional de Ética em Pesquisa e pela Agência Nacional de Vigilância Sanitária. Pesquisadores e patrocinadores alegam que o tempo para aprovação e início de ensaios clínicos limita novos estudos. No entanto, as normas brasileiras estão em contínuo aperfeiçoamento, o que demonstra interesse e capacidade em aprimorar os trâmites, sem perder a qualidade na avaliação ética

Mechanisms of T-Lymphocyte Accumulation during Experimental Pleural Infection Induced by Mycobacterium bovis BCG▿

Tuberculous pleurisy is a frequent extrapulmonary manifestation characterized by accumulation of fluid and inflammatory cells in the pleural space. Here, we investigated the mechanisms of T-lymphocyte accumulation in the pleural space by using a murine model of pleurisy induced by Mycobacterium bovis BCG. Intrathoracic (i.t.) injection of BCG (4.5 × 105 bacteria/cavity) induced accumulation of T lymphocytes in the pleural cavities of C57BL/6 mice. We observed the presence of CFU in pleural washes conducted 1, 2, 3, 7, and 15 days after pleurisy induction. Pretreatment with fucoidan inhibited T-lymphocyte accumulation at 1 day, but not at 15 days, after BCG-induced pleurisy. Accordingly, adoptive transfer of fluorescein isothiocyanate-labeled blood mononuclear cells to infected mice showed that T lymphocytes migrated into the pleural cavity 1 day (but not 15 days) after BCG injection. Cell-free pleural wash fluids recovered from mice 1 day after BCG i.t. stimulation (day 1 BCG-PW), but not day 7 or day 15 BCG-PW, induced in vitro T-cell transmigration, which was dependent on L-, P-, and E-selectins. In contrast, day 7 BCG-PW (but not day 1 BCG-PW) induced in vitro T-lymphocyte proliferation via interleukin-2 (IL-2) and gamma interferon (IFN-γ). Accordingly, in vivo IL-2 or IFN-γ neutralization abolished T-lymphocyte accumulation 7 days after pleurisy induction. Our results demonstrate that pleural infection induced by BCG leads to T-lymphocyte accumulation in two waves. The acute phase depends on selectin-mediated migration, while the second wave of T-lymphocyte accumulation seems to depend on a local proliferation induced by cytokines produced in situ

Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice

International audienceWound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long-term complications associated with diabetes mellitus. The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell recruitment and activation in inflamed skin; however, the role of regulatory T cells in wounds is still not clear. Our aim was to investigate the role of CCR4 and regulatory T cells in cutaneous wound healing in diabetic mice. Alloxan-induced diabetic wild-type mice (diabetic) developed wounds that were difficult to heal, differently from CCR4 e/e diabetic mice (CCR4 e/e diabetic), and also from anti-CCL17/22 or anti-CD25einjected diabetic mice that presented with accelerated wound healing and fewer regulatory T cells in the wound bed. Consequently, CCR4 e/e diabetic mice also presented with alteration on T cells population in the wound and draining lymph nodes; on day 14, these mice also displayed an increase of collagen fiber deposition. Still, cytokine levels were decreased in the wounds of CCR4 e/e diabetic mice on day 2. Our data suggest that the receptor CCR4 and regulatory T cells negatively affect wound healing in diabetic mice

Murine IL-17+ Vγ4 T lymphocytes accumulate in the lungs and play a protective role during severe sepsis

Submitted by sandra infurna ([email protected]) on 2016-04-18T16:50:53Z No. of bitstreams: 1 richard_valente_etal_IOC_2015.pdf: 1511614 bytes, checksum: 53c0a3196037eb84c301fc62a641a380 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-04-18T17:07:27Z (GMT) No. of bitstreams: 1 richard_valente_etal_IOC_2015.pdf: 1511614 bytes, checksum: 53c0a3196037eb84c301fc62a641a380 (MD5)Made available in DSpace on 2016-04-18T17:07:27Z (GMT). No. of bitstreams: 1 richard_valente_etal_IOC_2015.pdf: 1511614 bytes, checksum: 53c0a3196037eb84c301fc62a641a380 (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Farmacologia. Laboratório de Farmacologia Aplicada.. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas (INCT-IDN). Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Farmacologia. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Farmacologia. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil / Mount Sinai School of Medicine. New York City, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxinologia. Rio de Janeiro, RJ, Brasil.Faculdade de Medicina de Petrópolis. Laboratório de Imunologia. Petrópolis, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Farmacologia. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas (INCT-IDN). Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Ciências Biomédicas. Laboratório de Inflamação, Estresse Oxidativo e Câncer. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Farmacologia. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas (INCT-IDN). Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Background: Lung inflammation is a major consequence of the systemic inflammatory response caused by severe sepsis. Increased migration of γδ T lymphocytes into the lungs has been previously demonstrated during experimental sepsis; however, the involvement of the γδ T cell subtype Vγ4 has not been previously described. Methods: Severe sepsis was induced by cecal ligation and puncture (CLP; 9 punctures, 21G needle) in male C57BL/ 6 mice. γδ and Vγ4 T lymphocyte depletion was performed by 3A10 and UC3-10A6 mAb i.p. administration, respectively. Lung infiltrating T lymphocytes, IL-17 production and mortality rate were evaluated. Results: Severe sepsis induced by CLP in C57BL/6 mice led to an intense lung inflammatory response, marked by the accumulation of γδ T lymphocytes (comprising the Vγ4 subtype). γδ T lymphocytes present in the lungs of CLP mice were likely to be originated from peripheral lymphoid organs and migrated towards CCL2, CCL3 and CCL5, which were highly produced in response to CLP-induced sepsis. Increased expression of CD25 by Vγ4 T lymphocytes was observed in spleen earlier than that by αβ T cells, suggesting the early activation of Vγ4 T cells. The Vγ4 T lymphocyte subset predominated among the IL-17+ cell populations present in the lungs of CLP mice (unlike Vγ1 and αβ T lymphocytes) and was strongly biased toward IL-17 rather than toward IFN-γ production. Accordingly, the in vivo administration of anti-Vγ4 mAb abrogated CLP-induced IL-17 production in mouse lungs. Furthermore, anti-Vγ4 mAb treatment accelerated mortality rate in severe septic mice, demonstrating that Vγ4 T lymphocyte play a beneficial role in host defense. Conclusions: Overall, our findings provide evidence that early-activated Vγ4 T lymphocytes are the main responsible cells for IL-17 production in inflamed lungs during the course of sepsis and delay mortality of septic mice