Bromelain Inhibits Allergic Sensitization and Murine Asthma via Modulation of Dendritic Cells

The incidence of atopic conditions has increased in industrialized countries. Persisting symptoms and concern for drug side-effects lead patients toward adjunctive treatments such as phytotherapy. Previously, we have shown that Bromelain (sBr), a mixture of cysteine proteases from pineapple, Ananas comosus, inhibits ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). However, sBr’s effect on development of AAD when treatment is administered throughout OVA-alum sensitization was unknown and is the aim of the present study. C57BL/6J mice were sensitized with OVA/alum and challenged with 7 days OVA aerosol. sBr 6 mg/kg/0.5 ml or PBS vehicle were administered throughout sensitization. Lung, bronchoalveolar lavage (BAL), spleen, and lymph nodes were processed for flow cytometry and OVA-specific IgE was determined via ELISA. sBr treatment throughout OVA-alum sensitization significantly reduced the development of AAD (BAL eosinophils and lymphocytes). OVA-specific IgE and OVA TET+ cells were decreased. sBr reduced CD11c+ dendritic cell subsets, and in vitro treatment of DCs significantly reduced CD44, a key receptor in both cell trafficking and activation. sBr was shown to reduce allergic sensitization and the generation of AAD upon antigen challenge. These results provide additional insight into sBr's anti-inflammatory and antiallergic properties and rationale for translation into the clinical arena

A matemática financeira no ensino médio : uma nova visão

Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Exatas, Departamento de Matemática, Programa de Mestrado Profissional em Matemática em Rede Nacional, 2016.Nesse trabalho é apresentada uma proposta para o desenvolvimento da aprendizagem da Matemática Financeira no 3º ano do Ensino Médio por meio da Educação Financeira, utilizando situações cotidianas e focando num resultado mais significativo na vida do educando. O consumismo e a falta de planejamento se tornaram comum na realidade de grande parte da população. Com o advento da globalização e dos programas sociais do Governo Federal, criou-se a possibilidade de pessoas de quaisquer classes sociais terem acesso a bens de consumo, bem como obtenção de créditos com mais facilidade que outrora o teriam, criando um ciclo consumista. O principal objetivo é proporcionar uma nova visão sobre a matemática levando os alunos a refletirem sobre os diversos ângulos em que podem ser mostrados os assuntos de modo a desenvolver nos alunos uma vontade de aprender e avançar no estudo da Matemática Financeira que podem e devem ser aplicadas no dia-a-dia das pessoas.This work has as objective to present a proposal for the learning development of Financial Mathematics of the 3rd year of high school through Financial Education, using everyday situations and focusing in a more significant result in the student’s life. The consumerism and the lack of planning has become a usual reality of the majority of the population. With the advent of globalization and social programs of the Federal Government, it created the possibility of people from any social class to access consumer goods and to obtain credit more easily than before, creating a consumerist cycle. The main objective is to provide a new insight of mathematics leading students to reflect on the various angles that the subjects can be shown in order to develop in students a desire to learn and advance in Financial Mathematics study that can and should be applied on day-by-day lives

Cellular Interactions Occurring in the Hilar Lymph Node Mediate the Development of Tolerance in an Ovalbumin - Induced Murine Model of Allergic Airway Disease

Cellular Interactions Occurring in the Hilar Lymph Node Mediate the Development of Tolerance in an Ovalbumin - Induced Murine Model of Allergic Airway Disease Prabitha Natarajan, Ph.D. University of Connecticut, 2013 In a biphasic, ovalbumin (OVA)-induced murine asthma model where allergic airway disease (AAD) is followed by resolution and the development of local inhalational tolerance (LIT), transforming growth factor (TGF)-β expressing CD5+ B cells were selectively expanded locally in hilar lymph nodes (HLN) of LIT mice. When adoptively transferred, CD5+ B cells isolated from HLN of LIT mice but not CD5– B cells inhibited airway eosinophilia, in this OVA model. These CD5+ regulatory B cells (Breg) and CD4+ Foxp3+ T cells demonstrated similar increases in expression of chemokine receptors (CXCR4 and CXCR5) and localized in HLN B cell zones of LIT mice. LIT HLN CD5+ B cells, but not LIT HLN CD5– B cells, induced expression of Foxp3 in CD4+ CD25– T cells in vitro. In the mesenteric lymph node (MLN), the frequencies of Foxp3+ Tregs, CD5+ B cells and OVA-specific CD8+ T cells do not increase at AAD or LIT. Further, Foxp3+ Tregs did not localize in the MLN B cell zones of LIT mice. Thus, the expansion and preferential localization of regulatory cells in B cell zones occurs only in the HLN and is not observed in other mucosal sites such as the MLN. Studies with transgenic mice (HEL mice) expressing B cell receptor specific to the antigen- hen egg lysozyme (HEL) demonstrated that AAD develops normally in these mice in response the OVA antigen. Also, there was the induction of LIT in the HEL mice and the LIT HLN B cells from these mice induced expression of Foxp3 in CD4+ CD25– T cells in vitro similar to wild-type mice. Thus, Bregs are induced normally in the HLN upon chronic daily antigen exposure in an antigen non-specific manner

Bortezomib decreases the magnitude of a primary humoral immune response to transfused red blood cells in a murine model

BackgroundFew therapeutic options currently exist to prevent or to mitigate transfusion-associated red blood cell (RBC) alloimmunization. We hypothesized that bortezomib, a proteasome inhibitor currently being utilized for HLA alloantibody and ADAMTS13 autoantibody reduction, may be beneficial in a transfusion setting. Herein, we utilized a reductionist murine model to test our hypothesis that bortezomib would decrease RBC alloimmune responses.Study design and methodsWild-type mice were treated with bortezomib or saline and transfused with murine RBCs expressing the human KEL glycoprotein. Levels of anti-KEL immunoglobulins in transfusion recipients were measured by flow cytometry. The impact of bortezomib treatment on recipient plasma cells (PCs) and other immune cells was also assessed by flow cytometry and immunofluorescence.ResultsAfter bortezomib treatment, mice had a 50% reduction in splenic white blood cells and a targeted reduction in marrow PCs. Mice treated with bortezomib before the transfusion of KEL RBCs became alloimmunized in three of three experiments, although their serum anti-KEL IgG levels were 2.6-fold lower than those in untreated mice. Once a primary antibody response was established, bortezomib treatment did not prevent an anamnestic response from occurring.ConclusionTo the extent that these findings are generalizable to other RBC antigens and to humans, bortezomib monotherapy is unlikely to be of significant clinical benefit in a transfusion setting where complete prevention of alloimmunization is desirable. Given the impact on PCs, however, it remains plausible that bortezomib therapy may be beneficial for RBC alloimmunization prevention or mitigation if used in combination with other immunomodulatory therapies

CD4 Depletion or CD40L Blockade Results in Antigen-Specific Tolerance in a Red Blood Cell Alloimmunization Model

Approximately 3–10% of human red blood cell (RBC) transfusion recipients form alloantibodies to non-self, non-ABO blood group antigens expressed on donor RBCs, with these alloantibodies having the potential to be clinically significant in transfusion and pregnancy settings. However, the majority of transfused individuals never form detectable alloantibodies. Expanding upon observations that children initially transfused with RBCs at a young age are less likely to form alloantibodies throughout their lives, we hypothesized that “non-responders” may not only be ignorant of antigens on RBCs but instead tolerized. We investigated this question in a reductionist murine model, in which transgenic donors express the human glycophorin A (hGPA) antigen in an RBC-specific manner. Although wild-type mice treated with poly IC and transfused with hGPA RBCs generated robust anti-hGPA IgG alloantibodies that led to rapid clearance of incompatible RBCs, those transfused in the absence of an adjuvant failed to become alloimmunized. Animals depleted of CD4+ cells or treated with CD40L blockade prior to initial hGPA RBC exposure, in the presence of poly IC, failed to generate detectable anti-hGPA IgG alloantibodies. These non-responders to a primary transfusion remained unable to generate anti-hGPA IgG alloantibodies upon secondary hGPA exposure and did not prematurely clear transfused hGPA RBCs even after their CD4 cells had returned or their CD40L blockade had resolved. This observed tolerance was antigen (hGPA) specific, as robust IgG responses to transfused RBCs expressing a third-party antigen occurred in all studied groups. Experiments completed in an RBC alloimmunization model that allowed evaluation of antigen-specific CD4+ T-cells (HOD (hen egg lysozyme, ovalbumin, and human duffyb)) demonstrated that CD40L blockade prevented the expansion of ovalbumin 323-339 specific T-cells after HOD RBC transfusion and also prevented germinal center formation. Taken together, our data suggest that recipients may indeed become tolerized to antigens expressed on RBCs, with the recipient’s immune status upon initial RBC exposure dictating future responses. Although questions surrounding mechanism(s) and sustainability of tolerance remain, these data lay the groundwork for future work investigating RBC immunity versus tolerance in reductionist models and in humans