Chemokine receptor type 3 (CXCR3) plays an important role in CD8+ T cells migration during intracellular infections, such as Trypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been ...described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental to T. cruzi-specific CD8+ T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutely T. cruzi-infected mice decreased the number of specific CD8+ T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8+ T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8+ T cells interacted with plasmacytoid dendritic cells during infection by T. cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8+ T cells. Understanding which molecules and mechanisms guide CD8+ T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role in T. cruzi infection control.
CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main ...IFNγ producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where they may play their effector activities. Using a model of induction of resistance to highly susceptible A/Sn mice using an ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression was upregulated on CD8+ T-cells, which selectively migrated towards its ligands CXCL9 and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. cruzi infection in a way associated with hampered cytotoxic activity and increased proapoptotic markers on the H2KK-restricted TEWETGQI-specific CD8+ T-cells. Furthermore, CXCR3 receptor critically guided TEWETGQI-specific effector CD8+ T-cells to the infected heart tissue that express CXCL9 and CXCL10. Overall, our study pointed CXCR3 and its ligands as key molecules to drive T. cruzi-specific effector CD8+ T-cells into the infected heart tissue. The unveiling of the process driving cell migration and colonization of infected tissues by pathogen-specific effector T-cells is a crucial requirement to the development of vaccine strategies.
Background: Brazil has the world’s largest public organ transplant program, which was severely affected by the COVID-19 pandemic. The primary aim of the study was to evaluate differences in solid ...organ transplants and rejection episodes during the COVID-19 pandemic compared to the five years before the pandemic in the country. Methods: A seven-year database was built by downloading data from the DATASUS server. The pandemic period was defined as March 2020 to December 2021. The pre-pandemic period was from January 2015 to March 2020. Results: During the pandemic, the number of solid organ transplants decreased by 19.3% in 2020 and 22.6% in 2021 compared to 2019. We found a decrease for each evaluated organ, which was more pronounced for lung, pancreas, and kidney transplants. The seasonal plot of rejection data indicated a high rejection rate between 2018 and 2021. There was also an 18% (IRR 1.18 (95% CI 1.01 to 1.37), p = 0.04) increase in the rejection rate during the COVID-19 pandemic. Conclusions: The total number of organ transplants performed in 2021 represents a setback of six years. Transplant procedures were concentrated in the Southeast region of the country, and a higher proportion of rejections occurred during the pandemic. Together, these findings could have an impact on transplant procedures and outcomes in Brazil.
To report the experience of performing bronchoscopy in patients who underwent supportive therapy with extracorporeal membrane oxygenation in whom the bronchoscopy was performed.
This was a review of ...medical records of patients diagnosed with extracorporeal membrane oxygenation and who required diagnostic or therapeutic bronchoscopy. Records included were related to patients admitted to the intensive care unit of Hospital das Clínicas of Faculdade de Medicina of Universidade de São Paulo, between 2014 and 2020.
During the study, 16 bronchoscopies were performed in 8 patients admitted to the intensive care unit and who underwent supportive therapy with extracorporeal membrane oxygenation. The mean age of patients was 28.37 years. Four patients were women (50%). A total of 5 (31.25%) therapeutic bronchoscopies and 11 (68.75%) diagnostics were performed. In 5 of patients, material was collected: 4 samples of bronchoalveolar lavage, three collections of transbronchial biopsies, and 1 of endobronchial biopsies. No patient had radiological worsening or hemodynamic complications. One patient (6.25%) had transient desaturation. There was moderate bleeding after transbronchial biopsy in 1 (6.25%) procedure, which was resolved endoscopically.
Patients undergoing extracorporeal membrane oxygenation can safely perform diagnostic or therapeutic bronchoscopy provided that they have a detailed indication. Procedures were performed by a specialized bronchoscopy team in intensive care environment and with the assistance of a qualified multidisciplinary team in membrane oxygenation therapy extracorporeal.
Deficiency in memory formation and increased immunosenescence are pivotal features of
infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that ...consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of
, is a powerful strategy to elicit effector memory CD8
T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8
T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8
T response against
induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8
T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and
cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8
T-cells and the percentage of the polyfunctional population, which degranulated (CD107a
) and secreted both interferon gamma (IFNγ) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to
infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8
T-cells by mTOR inhibition after immunization, we showed that
proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8
T-cell response.
Toll-like receptors (TLRs) comprise the best-characterized pattern-recognition receptor (PRR) family able to activate distinct immune responses depending on the receptor/adaptor set assembled. TLRs, ...such as TLR2, TLR4 and TLR9, and their signaling were shown to be important in
infections. However, the role of the endosomal TLR3 in experimental paracoccidioidomycosys remains obscure.
assays, macrophages of the bone marrow of WT or TLR3
mice were differentiated for evaluation of their microbicidal activity.
, WT or TLR3
mice were infected intratracheally with
yeasts for investigation of the lung response type induced. The cytotoxic activity of CD8
T cells was assessed by cytotoxicity assay. To confirm the importance of CD8
T cells in the control of infection in the absence of tlr3, a depletion assay of these cells was performed. Here, we show for the first time that TLR3 modulate the infection against
by dampening pro-inflammatory response, NO production, IFN
CD8
T, and IL-17
CD8
T cell activation and cytotoxic function, associated with granzyme B and perforin down regulation. As conclusion, we suggest that TLR3 could be used as an escape mechanism of the fungus in an experimental paracoccidioidomycosis.
This work aims to approach the completeness and functionality of Thomas Kuhn’s conception about the Scientific Revolution inside the Normal Science and the concept of Paradigm in agreement with the ...construction of legal science. The analysis is presented through bibliographical research that considers not only the production of theorists dedicated to understanding the ordering of the History of Science, as well as Kuhn, but also of jurists who discuss the definition of Law and its changeability. In this perspective, the authors also study the influence of the aforementioned Revolution throughout the process of scientific evolution and how it can interfere in the organization of Law within society, from the explanation of the concepts shown by Kuhn in his work The Structure of Scientific Revolutions (1962) and from their analogy with the development of the social legal body. In conclusion, the deliberation regarding the Scientific Revolution is configured as a model to be followed to overcome the crises faced by Law, through the change of Paradigm, so that there is the guarantee and effectiveness of legal prerogatives bequest to the collectivity.
Tumor-associated carcinoembryonic antigen (CEA) is a natural target for vaccines against colorectal cancers. Our previous experience with a DNA vaccine with scFv6.C4, a CEA surrogate, showed a ...CEA-specific immune response with 40% of tumor-free mice after challenge with B16F10-CEA and 47% with MC38-CEA cells. These percentages increased to 63% after using FrC as an adjuvant. To further enhance the vaccine efficacy, we tested GM-CSF and IFNγ as adjuvants. C57BL/6J-CEA2682 mice were immunized 4 times with uP-PS/scFv6.C4, uP-PS/scFv6.C4 + uP-IFNγ, or uP-PS/scFv6.C4 + uP-GMCSF. After one week, the mice were challenged with MC38-CEA, and tumor growth was monitored over 100 days. Immunization with scFv6.C4 and scFv6.C4 + GM-CSF resulted in a gradual increase in the anti-CEA antibody titer, while scFv6.C4 + IFNγ immunization led to a rapid and sustained increase in the titer. The addition of IFNγ also induced higher CD4 + and CD8 + responses. When challenged, almost 80% of the scFv6.C4 + IFNγ-vaccinated mice did not develop tumors, while the others had a significant tumor growth delay. The probability of being tumor-free was 2700% higher using scFv6.C4 + IFNγ than scFv6.C4. The addition of GM-CSF had no additional effect on tumor protection. DNA immunization with scFv6.C4 + IFNγ, but not GM-CSF, increased the antitumor effect via readily sustained specific humoral and cytotoxic responses to CEA.
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