The Blockade of Interleukin-2 During the Acute Phase of Trypanosoma cruzi Infection Reveals Its Dominant Regulatory Role.

Trypanosoma cruzi infection causes Chagas' disease in humans. The infection activates the innate and adaptative immunity in an orchestrated immune response to control parasite growth, guaranteeing host survival. Despite an effective immune response to the parasite in the acute phase, the infection progresses to a chronic stage. The parasite infects different tissues such as peripheral neurons, the brain, skeletal muscle, and heart muscle, among many others. It is evident now that tissue-specific immune responses may develop along with anti-parasite immunity. Therefore, mechanisms to regulate immunity and to ensure tissue-specific tolerance are operating during the infection. Studying those immunoregulatory mechanisms is fundamental to improve host protection or control inflammatory reactions that may lead to pathology. The role of IL-2 during T. cruzi infection is not established. IL-2 production by T cells is strongly down-modulated early in the disease by unknown mechanisms and remains low during the chronic phase of the disease. IL-2 activates NK cells, CD4, and CD8 T cells and may be necessary to immunity development. Also, the expansion and maintenance of regulatory T cells require IL-2. Thus, IL-2 may be a key cytokine involved in promoting or down-regulating immune responses, probably in a dose-dependent manner. This study blocked IL-2 during the acute T. cruzi infection by using a neutralizing monoclonal antibody. The results show that parasitemia and mortality rate was lower in animals treated with anti-IL-2. The percentages and total numbers of CD4+CD25+Foxp3+ T cells diminished within three weeks of infection. The numbers of splenic activated/memory CD4 and CD8 splenic T cells increased during the acute infection. T cells producing IFN-γ, TNF-α and IL-10 also augmented in anti-IL-2-treated infected mice. The IL-2 blockade also increased the numbers of inflammatory cells in the heart and skeletal muscles and the amount of IL-17 produced by heart T cells. These results suggest that IL-2 might be involved in the immune regulatory response during the acute T. cruzi infection, dampening T cell activation through the expansion/maintenance of regulatory T cells and regulating IL-17 production. Therefore, the IL-2 pathway is an attractive target for therapeutic purposes in acute and chronic phases of Chagas' disease.

Repercussões da doença celíaca na qualidade de vida de sujeitos adultos / The celiac disease impact towards the adults' life quality / Repercusiones de la enferida celiaca en la calidad de vida de sujetos adultos

Objective: The study's purpose has been to further understand the repercussions that Celiac Disease has on the adults' life quality. Methods: It is an integrative literature review, which has used the following databases for the selection of articles published between 2006 and 2017: LILACS, VHL, SciELO, MEDLINE, CINHAL and CAPES periodic portal. Results: Twenty articles were fully scrutinized. Based on the content analysis stages, the following three categories appeared: Eating practices of adults bearing the Celiac Disease; Quality of life of the Celiac Disease bearing adult; Importance of the patient care team in the diagnosis and follow-up of adults bearing the Celiac Disease. Conclusion: It is expected that science finds other means of treatment, in addition to the restrictive diet and/or the fact that the industry may adapt to the needs of adult subjects, by offering quality products and low cost, for inclusive and sociable access, then reducing the suffering generated by the disease

Objetivo: Compreender as repercussões que a Doença Celíaca acarreta na qualidade de vida do sujeito adulto, por meio de uma revisão integrativa. Método: Revisão integrativa, com buscas nas bases de dados LILACS, BVS, SciELO, MEDLINE, CINHAL e portal de periódicos CAPES, com seleção de artigos publicados entre 2006 e 2017.Resultados: Foram analisados 20 artigos ao final na íntegra. Pautada nas etapas de análise de conteúdo, três categorias emergiram: Práticas alimentares do adulto com Doença Celíaca; Qualidade de vida do adulto com Doença Celíaca; Importância da equipe multiprofissional de saúde no diagnóstico e acompanhamento do adulto com Doença Celíaca. Conclusão: A perspectiva de que a ciência encontre outros meios de tratamento, além da dieta restritiva e/ou a indústria se adeque às necessidades dos sujeitos adultos, por meio da oferta de produtos de qualidade e baixo custo, para o acesso inclusivo e sociável, diminuindo o sofrimento gerado pela doença

Objetivo: Comprender las repercusiones que la Enfermedad Celíaca acarrea en la calidad de vida del sujeto adulto, por medio de una revisión integrativa. Método: La revisión integrativa, con búsquedas en las bases de datos LILACS, BVS, SciELO, MEDLINE, CINHAL y portal de revistas CAPES, con selección de artículos publicados entre 2006 y 2017. Resultados: Se analizaron 20 artículos al final en su totalidad. En las etapas de análisis de contenido, tres categorías emergieron: Prácticas alimentarias del adulto con enfermedad celíaca; Calidad de vida del adulto con enfermedad celiaca; Importancia del equipo multiprofesional de salud en el diagnóstico y acompañamiento del adulto con enfermedad celíaca. Conclusión: La perspectiva de que la ciencia encuentre otros medios de tratamiento, además de la dieta restrictiva y / o la industria se adecue a las necesidades de los sujetos adultos, a través de la oferta de productos de calidad y bajo costo, para el acceso inclusivo y sociable, disminuyendo el sufrimiento generado por la enfermedad

Participação das células T de memória e linfócitos CD4. CD25+Foxp3 (reguladores) nos mecanismos de resistência à infecção experimental pelo trypanosoma cruzi / Participation of memory T cells and Foxp3 + lymphocytes CD4. CD25 (regulators) in the mechanisms of resistance to experimental infection with Trypanosoma cruzi

A infecção pelo Trypanosoma cruzi (T. cruzi) resulta em uma resposta imune que controla a predominância do parasito, mas é incapaz de eliminá-lo completamente, levando a persistência do parasito. A gravidade da doença de Chagas está correlacionada com a persistência do parasito nos tecidos musculares, neurais e intestinais. A função imunorregulatória das células T reguladoras em limitar a resposta imune poderia ser explorada no sentido de erificar a sua quantidade e qualidade no modelo experimental de infecção por T. cruzi. O principal objetivo deste projeto foi estudar a participação e influência dos linfócitos Treg sobre os mecanismos de resistência a infecção por T. cruzi, principalmente sobre a geração/manutenção de células T CD4+ e CD8+ memória efetora e central. Para tal, foi realizado um estudo comparativo da importância dos linfócitos T, e alterações das células Treg na infecção experimental por T. cruzi, de animais susceptíveis (C57Bl/6) e resistentes (BALB/c) nos dias 10, 20 e 30 apos a infecção. Adicionalmente, com o objetivo de investigar o papel das células T reguladoras, foi realizada a neutralização da citocina IL-2, com o tratamento in vivo com anti-IL-2 monoclonal (clone JES6-1A12), em animais C57Bl/6, durante a infecção com a cepa Tulahuen de T. cruzi. A análise da cinética de infecção (10, 20 e 30 dias) revelou que os animais resistentes (BALB/c) apresentaram maior expansão de células T efetoras CD4+ e CD8+ no baço e no tecido muscular esquelético. Os dados coletados demonstram que o tratamento com anti-IL-2 resultou em diminuição significativa da população de células T CD4+CD25+Foxp3+ nos animais infectados, comparado ao grupo infectado e tratado com imunoglobulina de rato. A diminuição das células Treg nestes animais resultou em alterações importantes nos mecanismos efetores como, por exemplo: o aumento da expansão das células T CD4+ e CD8+ efetoras e a produção de citocinas pró-inflamatórias e anti-inflamatórias no baço e tecido muscular esquelético. O reflexo destas alterações foi relacionado à diminuição da parasitemia e da mortalidade dos animais. Desta forma, as células Treg parecem exercer um controle da resposta imune efetora ao T. cruzi no sentido de tentar controlar a disseminação do patógeno e, ao mesmo tempo, impedir a destruição tecidual decorrente de uma exacerbação da resposta imune. Portanto, sugere-se que as células Treg estariam participando da resposta imune ao T. cruzi no sentido de modular a resposta imune efetora.

Enhancement of experimental cutaneous leishmaniasis by Leishmania molecules is dependent on interleukin-4, serine protease/esterase activity, and parasite and host genetic backgrounds.

Most inbred strains of mice, like the BALB/c strain, are susceptible to Leishmania amazonensis infections and resistant to Leishmania braziliensis infections. This parasite-related difference could result from the activity of an L. amazonensis-specific virulence factor. In agreement with this hypothesis, it is shown here that the intravenous injection of BALB/c mice with L. amazonensis amastigote extract (LaE) but not the L. braziliensis extract confers susceptibility to L. braziliensis infection. This effect was associated with high circulating levels of IgG1 anti-L. amazonensis antibodies and with an increase in interleukin-4 (IL-4) production and a decrease in gamma interferon production by draining lymph node cells. Moreover, the effect was absent in IL-4-knockout mice. The biological activity in the LaE was not mediated by amphiphilic molecules and was inhibited by pretreatment of the extract with irreversible serine protease inhibitors. These findings indicate that the LaE contains a virulence-related factor that (i) enhances the Leishmania infection by promoting Th2-type immune responses, (ii) is not one of the immunomodulatory Leishmania molecules described so far, and (iii) is either a serine protease or has an effect that depends on that protease activity. In addition to being Leishmania species specific, the infection-enhancing activity was also shown to depend on the host genetic makeup, as LaE injections did not affect the susceptibility of C57BL/6 mice to L. braziliensis infection. The identification of Leishmania molecules with infection-enhancing activity could be important for the development of a vaccine, since the up- or downmodulation of the immune response against a virulence factor could well contribute to controlling the infection.

The ACE inhibitors enalapril and captopril modulate cytokine responses in Balb/c and C57Bl/6 normal mice and increase CD4(+)CD103(+)CD25(negative) splenic T cell numbers.

Increasing evidence implies beneficial effects of angiotensin-converting enzyme (ACE) inhibitors beyond those of their original indications to control hypertension. One of the most attractive non-hemodynamic properties of ACE inhibitors is their ability to regulate cytokine production. The mechanism(s) underlying the role of ACE inhibitors on cytokine synthesis are not well understood but they have traditionally been attributed to the inhibition of angiotensin (Ang) II formation. In fact, it has been extensively demonstrated that ACE inhibitors decrease Ang II-induced production of proinflammatory cytokines and chemokines. However, it is not well described if inhibition of endogenous Ang II generation by ACE inhibitors modulates systemic cytokine production in mice. To verify that, in this work, we investigated the effects of treatment with the ACE inhibitors enalapril and captopril on cytokine synthesis in C57Bl/6 and Balb/c mice. Our results show that enalapril up regulates IL-10 produced by splenocytes from Balb/c and C57Bl/6 mice and captopril increased it only in Balb/c mice. Furthermore, CD4(+)CD103(+) presented increased IL-10 production after enalapril treatment. Enalapril as well as captopril short-term treatment enhanced IL-2 synthesis in Balb/c mice. Besides, enhanced IL-2 and IL-10 levels correlates with increased CD4(+)CD103(+)CD25(negative) T cells numbers in spleens from enalapril-treated mice.

Requirement of L-selectin for gammadelta T lymphocyte activation and migration during allergic pleurisy: co-relation with eosinophil accumulation.

Intra-thoracic antigenic challenge (ovalbumin, 12.5 microg/cavity) led to increased numbers of gammadelta T lymphocytes in pleural cavities, blood and thoracic lymph nodes in sensitized mice within 48 h. Part of these cells expressed CD62L, which increased on gammadelta T cell surfaces obtained from lymph nodes after ovalbumin (OVA) challenge. Selectin blockade by fucoidan pre-treatment (10 mg/kg, i.v.) impaired in vivo increase in CD25(+) and c-fos(+) gammadelta T cell numbers in lymph nodes, indicating a role for selectins on gammadelta T lymphocyte activation and proliferation. In vivo selectin blockade by fucoidan or alpha-CD62L mAb (200 microg/mice, i.p.) also inhibited OVA-induced gammadelta T cell accumulation in pleural cavities. Confirming the direct effect of CD62L on gammadelta T cell transmigration, the migration of i.v. adoptively-transferred CFSE-labeled gammadelta T lymphocytes into pleural cavities of challenged recipient mice was impaired by fucoidan ex vivo treatment. It is noteworthy that eosinophil influx was also impaired in those mice, indicating that reduced eosinophil migration by CD62L in vivo blockade depended on gammadelta T cell migration via CD62L molecules. Accordingly, pleural gammadelta T lymphocytes from fucoidan-treated mice presented reduced OVA-induced IL-5 and CCL11 production. Supporting these data, the depletion of Vgamma4 T lymphocytes, which are pulmonary gammadelta T cells, decreased OVA-induced eosinophil influx into allergic site. Such results demonstrate that CD62L is crucial for the activation of gammadelta T cells in lymph nodes, for their migration into inflamed tissue and for the modulation of eosinophil influx during allergic response.

Long-term administration of IgG2a anti-NK1.1 monoclonal antibody ameliorates lupus-like disease in NZB/W mice in spite of an early worsening induced by an IgG2a-dependent BAFF/BLyS production.

The role of natural killer (NK) T cells in the development of lupus-like disease in mice is still controversial. We treated NZB/W mice with anti-NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti-NK1.1 mAb increased the production of anti-dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti-NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus-like disease. Augmented titres of anti-dsDNA in NZB/W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti-NK1.1 mAb reduced the levels of interleukin-16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti-dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B-cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B-cell activity for the production of anti-dsDNA. We concluded that NK T cells are involved in the progression of lupus-like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology.

B cells modulate T cells so as to favour T helper type 1 and CD8+ T-cell responses in the acute phase of Trypanosoma cruzi infection.

In this study, we have evaluated the production of pro- and anti-inflammatory cytokines and the formation of central and effector memory T cells in mice lacking mature B cells (mu MT KO). The results show that Trypanosoma cruzi infection in C57Bl/6m mu MT KO mice is intensified in relation to control mice and this exacerbation is related to low levels of inflammatory cytokines produced during the acute infection and the lower numbers of central and effector memory CD4(+) and CD8(+) T cells generated during the acute phase of the infection. In addition, a marked reduction in the CD8(+) T-cell subpopulation was observed in mu MT KO infected mice. In agreement to this, the degree of tissue parasitism was increased in mu MT mice and the tissue inflammatory response was much less intense in the acute phase of the infection, consistent with a deficit in the generation of effector T cells. Flow cytometry analysis of the skeletal muscle inflammatory infiltrate showed a predominance of CD8(+) CD45Rb low in B-cell-sufficient C57Bl/6 mice, whereas the preponderant cell type in mu MT KO skeletal muscle inflammatory infiltrate was CD4(+) T cells. In addition, CD8(+) T cells found in skeletal muscle from mu MT KO infected mice were less activated than in control B-cell sufficient infected mice. These results suggest that B cells may participate in the generation of effector/memory T cells. In addition and more importantly, B cells were crucial in the maintenance of central and effector memory CD8(+) T cell, as well as the determination of the T cell cytokine functional pattern, and they may therefore account for critical aspects of the resistance to intracellular pathogens, such as T. cruzi.

Leishmania amazonensis: participation of regulatory T and B cells in the in vitro priming (PIV) of CBA/J spleen cells susceptible response.

CBA/J mice are resistant to Leishmania major and susceptible to Leishmania amazonensis. Early events determine infection outcome. Until now, PIV (in vitro priming) immune response to L. amazonensis has not been assessed. Herein, we have shown that compared to L. major, L. amazonensis induced higher parasite burden associated to similar IL-4, IFN-gamma, and TNF-alpha mRNA expressions and IFN-gamma and IL-10 levels. Although similar amounts of IL-10 were detected, the frequency of intracellular IL-10 positive B cells was enhanced in spleen cells stimulated with anti-CD3/anti-CD28, or anti-CD3/anti-CD28 and L. amazonensis, compared to L. major-stimulation. Interestingly, IL-10- producing B cells were reduced in response to anti-CD3/anti-CD28 stimulation combined with L. major compared to the other groups. L. amazonensis may favor T regulatory cell development, since 40% of all the CD4+CD25+ were CD25(high) cells. These data suggest that in PIV, susceptibility to L. amazonensis is not related to Th cell polarization, but to the presence and activity of regulatory T and B cells.

Estudo da migração de células T NK1.1+NO músculo estriado, durante a infecção experimental pelo trypanosoma cruzi em animais desprovidos de linfócitos B funcionais / Evaluation of NK1.1 + T cells and inflammatory response in skeletal muscle of uMT mice, during experimental infection by trypanosoma cruzi

Foi anteriormente demonstrado que as células NK (Natural Killer) estão relacionadas às bases para resistência à infecção por Trypanosoma cruzi, pois a depleção de células positivas para NK1.1+ resulta em alta parasitemia de camundongos C57Bl/6 infectados pelo T. cruzi. Estudos de nossa equipe indicaram ainda que as células T NK1.1+ poderiam induzir a formação de células T efetoras / memória, e que a resistência à infecção foi correlacionada com a quantidade de células T CD4+ CD45RB presentes antes da infecção. No presente estudo avaliamos a função regulatória de células T NK1.1+ durante a infecção experimental pelo T. cruzi, na ausência de linfócitos B. (...) Sugere-se, portanto que as células T CD4+ NK1.1+ poderiam ser regulatórias no sentido de apresentar atividade anti-inflamatória e que as células aß+NK1.1+ exerceriam função auxiliar na geração de células T efetoras/memória em nosso sistema experimental.