The Wiskott-Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells

The Wiskott-Aldrich syndrome, a primary human immunodeficiency, results from defective expression of the hematopoietic-specific cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP). Because CD4+CD25+Foxp3+ naturally occurring regulatory T (nTreg) cells control autoimmunity, we asked whether colitis in WASP knockout (WKO) mice is associated with aberrant development/function of nTreg cells. We show that WKO mice have decreased numbers of CD4+CD25+Foxp3+ nTreg cells in both the thymus and peripheral lymphoid organs. Moreover, we demonstrate that WKO nTreg cells are markedly defective in both their ability to ameliorate the colitis induced by the transfer of CD45RBhi T cells and in functional suppression assays in vitro. Compared with wild-type (WT) nTreg cells, WKO nTreg cells show significantly impaired homing to both mucosal (mesenteric) and peripheral sites upon adoptive transfer into WT recipient mice. Suppression defects may be independent of antigen receptor–mediated actin rearrangement because both WT and WKO nTreg cells remodeled their actin cytoskeleton inefficiently upon T cell receptor stimulation. Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor–mediated activation, substantially rescues the suppression defects. WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10. Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency

Sonodynamic and Photodynamics Used as a Combined Therapy in the Treatment of Malignant Neoplasms: Facts and Open Questions

Photodynamic therapy (PDT) used in combination with sonodynamic therapy (SDT) is a new approach that aims to increase the effectiveness of tumor treatment when compared to the effect of each independent therapy. PDT is based on stimulating sensitizers with photons, while the most accepted theory for SDT is that sensitizers are stimulated by the sonoluminescence phenomenon. However, after the excitation of the sensitizer, both therapies follow a common path, leading to the generation of free radicals and inducing cell death. One of the positive aspects of this combination is the augmentation of anti-tumor activity with fewer side effects, since cell death may be induced using lower sensitizer concentrations or less exposure to ultrasound or light. Another benefit of combining PDT and SDT, especially with the use of low-frequency ultrasound is the induction of sonophoresis. For instance, on the skin, it may facilitate the absorption of the sensitizer. However, research involving both PDT and SDT exhibit many variants, including differences in irradiation sources and their intensities, among others. These aspects contribute to a lack of standardization, leading to result variations, hindering assessment on the real contribution that these combined therapies can offer in tumor treatment. Thus, further research in the pre-clinical and clinical areas are crucial

Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability

Signal integration duringT lymphocyte activation and function: lessons from the Wiskott–Aldrich syndrome

Made available in DSpace on 2015-08-19T13:49:20Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) vinicius_almeida_etal_IOC-2015.pdf: 1082183 bytes, checksum: 93e3b426efdf1ea400c869adeed7545f (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.UMR 1043, Centre de Physiopathologie de Toulouse Purpan. INSERM. Toulouse, France / Université Toulouse III Paul-Sabatier. Toulouse, France / UMR 5282, CNRS. Toulouse, France.UMR 1043, Centre de Physiopathologie de Toulouse Purpan. INSERM. Toulouse, France / Université Toulouse III Paul-Sabatier. Toulouse, France / UMR 5282, CNRS. Toulouse, France.Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Rio de Janeiro, RJ, Brasil.Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes fromWiskott–Aldrich syndrome (WAS) patients.WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss howfurther study ofWAS may contribute to solve novel challenges of T lymphocyte biology

Transfusion medicine in medical education: an analysis of curricular grids in Brazil and a review of the current literature

Submitted by Sandra Infurna ([email protected]) on 2016-12-30T13:59:59Z No. of bitstreams: 1 marcella_vaena_etal_IOC_2016.pdf: 482501 bytes, checksum: a881b92bacd1b0c807d379e53d3d92a3 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2016-12-30T14:08:30Z (GMT) No. of bitstreams: 1 marcella_vaena_etal_IOC_2016.pdf: 482501 bytes, checksum: a881b92bacd1b0c807d379e53d3d92a3 (MD5)Made available in DSpace on 2016-12-30T14:08:30Z (GMT). No. of bitstreams: 1 marcella_vaena_etal_IOC_2016.pdf: 482501 bytes, checksum: a881b92bacd1b0c807d379e53d3d92a3 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Universidade Estácio de Sá (UNESA). Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil

Surmounting the obstacles that impede effective CAR T cell trafficking to solid tumors

International audienceInnovative immunotherapies based on immune checkpoint targeting antibodies and engineered T cells are transforming the way we approach cancer treatment. However, although these T cell centered strategies result in marked and durable responses in patients across many different tumor types, they provide therapeutic efficacy only in a proportion of patients. A major challenge of immuno-oncology is thereby to identify mechanisms responsible for resistance to cancer immunotherapy in order to overcome them via adapted strategies that will ultimately improve intrinsic efficacy and response rates. Here, we focus on the barriers that restrain the trafficking of chimeric antigen receptor (CAR)-expressing T cells to solid tumors. Upon infusion, CAR T cells need to home into malignant sites, navigate within complex tumor environments, form productive interactions with cancer cells, deliver their cytotoxic activities, and finally persist. We review the accumulating evidence that the microenvironment of solid tumors contains multiple obstacles that hinder CAR T cells in the dynamic steps underlying their trafficking. We focus on how these hurdles may in part account for the failure of CAR T cell clinical trials in human carcinomas. Given the engineered nature of CAR T cells and possibilities to modify the tumor environment, there are ample opportunities to augment CAR T cell ability to efficiently find and combat tumors. We present some of these strategies, which represent a dynamic field of research with high potential for clinical applicability

Transfusion medicine in medical education: an analysis of curricular grids in Brazil and a review of the current literature

ABSTRACT BACKGROUND: Blood transfusions are one of the most performed medical procedures in the world. Thus, as education in transfusion medicine is vital to medical care, it should aim to promote a responsible practice with the rational use of blood by doctors. This study aims to investigate the situation of the teaching of transfusion medicine in medical schools in Brazil. METHOD: The websites of the 249 Brazilian medical schools in operation in June 2015 were visited and the curricula of the medical courses were investigated in respect to the presence or absence of a transfusion medicine discipline. When available, the subject grids were analyzed to verify whether a description of content regarding transfusion medicine was given within other disciplines. RESULTS: Of the 249 medical school sites visited, information on the curriculum was obtained from 178. Of the medical schools that published their curriculum, 132 (74.1%) did not have disciplines of transfusion medicine or hematology and only seven (3.9%) had a discipline of transfusion medicine in the curricular grid. CONCLUSIONS: Education on transfusion medicine is of fundamental importance for safe and efficient transfusion practices. Deficiencies in medical knowledge of this subject have been found worldwide. The results of this study indicate a possible deficiency in teaching the basics of this specialty. Thus, additional prospective studies to assess the knowledge and practice of transfusion medicine in Brazilian medical schools are warranted, which could prompt a discussion on the importance of offering training in transfusion medicine to medical students

Is the thymus a target organ in infectious diseases?

The thymus is a central lymphoid organ, in wich T cell precursors differentiale and generate most of the so-called T cell reprtoire. Along with a variety of acute infectious diseases, we and others determined important changes in both microenvironmental and lymphoid compartments of the organ. For example, one major and common feature observed in acute viral, bacterial and parasitic diseases, is a depletion of cortical thymocytes, mostly those bearing the CD4-CD8 double positive phenotype. This occurs simmultaneously to the relative enrichment in medullary CD4 or CD8 single positive cells, expressing high densities of the CD3 complex. Additionally we noticed a variety of changes in the thymic microenvironment (and particularly is epithelial component), comprising abnormal location of thymic epithelial cell subsets as well has a denser Ia-bearing cellular network. Moreover, the extracellular matrix network was altered with an intralobular increase of basement membrane proteins that positively correlated with the degree of thymocyte death. Lastly, anti-thymic cell antibodies were detected in both human and animal models of infectious diseases, and in some of them a phenomenon of molecular mimicry could be evidenced. Taken together, the data receiwed herein clearly show that the thymus should be regarded as a target in infectious diseases

Trypanosoma cruzi entrance through systemic or mucosal infection sites differentially modulates regional immune response following acute infection in mice

Submitted by sandra infurna ([email protected]) on 2016-02-07T21:52:00Z No. of bitstreams: 1 juliana2_demeis_etal_IOC_2013.pdf: 590940 bytes, checksum: 6cfe3971464389bf8aa06f9ff23d88ef (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-02-07T22:02:49Z (GMT) No. of bitstreams: 1 juliana2_demeis_etal_IOC_2013.pdf: 590940 bytes, checksum: 6cfe3971464389bf8aa06f9ff23d88ef (MD5)Made available in DSpace on 2016-02-07T22:02:49Z (GMT). No. of bitstreams: 1 juliana2_demeis_etal_IOC_2013.pdf: 590940 bytes, checksum: 6cfe3971464389bf8aa06f9ff23d88ef (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, BrasilAcute Chagas disease is characterized by a systemic infection that leads to the strong activation of the adaptive immune response. Outbreaks of oral contamination by the infective protozoan Trypanosoma cruzi are frequent in Brazil and other Latin American countries, and an increased severity of clinical manifestations and mortality is observed in infected patients. These findings have elicited questions about the specific responses triggered after T. cruzi entry via mucosal sites, possibly modulating local immune mechanisms, and further impacting regional and systemic immunity. Here, we provide evidence for the existence of differential lymphoid organ responses in experimental models of acute T. cruzi infection

Sphingosine-1-Phosphate Receptor 1 Is Involved in Non-Obese Diabetic Mouse Thymocyte Migration Disorders

NOD (non-obese diabetic) mice spontaneously develop type 1 diabetes following T cell-dependent destruction of pancreatic β cells. Several alterations are observed in the NOD thymus, including the presence of giant perivascular spaces (PVS) filled with single-positive (SP) CD4+ and CD8+ T cells that accumulate in the organ. These cells have a decreased expression of membrane CD49e (the α5 integrin chain of the fibronectin receptor VLA-5 (very late antigen-5). Herein, we observed lower sphingosine-1-phosphate receptor 1 (S1P1) expression in NOD mouse thymocytes when compared with controls, mainly in the mature SP CD4+CD62Lhi and CD8+CD62Lhi subpopulations bearing the CD49e− phenotype. In contrast, differences in S1P1 expression were not observed in mature CD49e+ thymocytes. Functionally, NOD CD49e− thymocytes had reduced S1P-driven migratory response, whereas CD49e+ cells were more responsive to S1P. We further noticed a decreased expression of the sphingosine-1-phosphate lyase (SGPL1) in NOD SP thymocytes, which can lead to a higher sphingosine-1-phosphate (S1P) expression around PVS and S1P1 internalization. In summary, our results indicate that the modulation of S1P1 expression and S1P/S1P1 interactions in NOD mouse thymocytes are part of the T-cell migratory disorder observed during the pathogenesis of type 1 diabetes