Institute for Investigation in Immunology

São Paulo, Brazil

Institute for Investigation in Immunology

São Paulo, Brazil

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Coelho V.,University of Sao Paulo | Coelho V.,Institute for Investigation in Immunology | Saitovitch D.,Institute for Investigation in Immunology | Saitovitch D.,Grande Rio University | And 4 more authors.
Current Opinion in Organ Transplantation | Year: 2013

PURPOSE OF REVIEW: To discuss the B-cell diverse functions in organ transplantation, highlighting the emerging debate on the role of regulatory B cells (Bregs). We underscore the need to re-examine and integrate data on B-cell functional activities, aiming to discriminate their regulatory (REG) and inflammatory (INFLAMMA) functions and to translate this knowledge for the development of novel immunomodulatory therapeutic strategies and to rethink the current ones. RECENT FINDINGS: Data from both experimental models and clinical trials point that B cells of various phenotypes have immunoregulatory activity and play an important role in controlling graft inflammation. Data on the state of operational tolerance, in kidney transplantation, suggest the relevance of preserving a healthy B-cell compartment-in numbers and in the Breg capacity to activate the CD40/STAT3 signalling pathway-for achieving and maintaining homeostasis. Moreover, autoantibodies also comprise transplant immunobiology and it seems that not all alloantibodies are deleterious. SUMMARY: The role of B cells, in organ transplantation, can no longer be taken as mere generators of plasma cells, which produce alloantibodies deleterious to the graft. B cells also seem to integrate a complex immunoregulatory network in organ transplantation, with Bregs of various phenotypes and possibly also antibodies. The functional discrimination of REG/INFLAMMA B-cell roles needs to be considered in the clinical setting. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Moraes-Vieira P.M.M.,University of Sao Paulo | Moraes-Vieira P.M.M.,Institute for Investigation in Immunology | Takenaka M.C.S.,University of Sao Paulo | Takenaka M.C.S.,Institute for Investigation in Immunology | And 11 more authors.
Clinical Immunology | Year: 2012

Some organ-transplanted patients achieve a state of "operational tolerance" (OT) in which graft function is maintained after the complete withdrawal of immunosuppressive drugs. We used a gene panel of regulatory/inflammatory molecules (FOXP3, GATA3, IL10, TGFB1, TGFBR1/ TBX21, TNF and IFNG) to investigate the gene expression profile in peripheral blood mononuclear cells of renal-transplanted individuals experiencing OT compared to transplanted individuals not displaying OT and healthy individuals (HI). OT subjects showed a predominant regulatory (REG) profile with higher gene expression of GATA3, FOXP3, TGFB1 and TGFB receptor 1 compared to the other groups. This predominant REG gene expression profile displayed stability over time. The significant GATA3 gene and protein expressions in OT individuals suggest that a Th2 deviation may be a relevant pathway to OT. Moreover, the capacity of the REG/INFLAMMA gene panel to discriminate OT by peripheral blood analysis indicates that this state has systemic repercussions. © 2011 Elsevier Inc.


Deng X.,Blood Systems Research Institute | Sabino E.C.,University of Sao Paulo | Cunha-Neto E.,University of Sao Paulo | Cunha-Neto E.,Institute for Investigation in Immunology | And 7 more authors.
PLoS ONE | Year: 2013

Background: Familial aggregation of Chagas cardiac disease in T. cruzi-infected persons suggests that human genetic variation may be an important determinant of disease progression. Objective: To perform a GWAS using a well-characterized cohort to detect single nucleotide polymorphisms (SNPs) and genes associated with cardiac outcomes. Methods: A retrospective cohort study was developed by the NHLBI REDS-II program in Brazil. Samples were collected from 499 T. cruzi seropositive blood donors who had donated between1996 and 2002, and 101 patients with clinically diagnosed Chagas cardiomyopathy. In 2008-2010, all subjects underwent a complete medical examination. After genotype calling, quality control filtering with exclusion of 20 cases, and imputation of 1,000 genomes variants; association analysis was performed for 7 cardiac and parasite related traits, adjusting for population stratification. Results: The cohort showed a wide range of African, European, and modest Native American admixture proportions, consistent with the recent history of Brazil. No SNPs were found to be highly (P<10-8) associated with cardiomyopathy. The two mostly highly associated SNPs for cardiomyopathy (rs4149018 and rs12582717; P-values <10-6) are located on Chromosome 12p12.2 in the SLCO1B1 gene, a solute carrier family member. We identified 44 additional genic SNPs associated with six traits at P-value <10-6: Ejection Fraction, PR, QRS, QT intervals, antibody levels by EIA, and parasitemia by PCR. Conclusion: This GWAS identified suggestive SNPs that may impact the risk of progression to cardiomyopathy. Although this Chagas cohort is the largest examined by GWAS to date, (580 subjects), moderate sample size may explain in part the limited number of significant SNP variants. Enlarging the current sample through expanded cohorts and meta-analyses, and targeted studies of candidate genes, will be required to confirm and extend the results reported here. Future studies should also include exposed seronegative controls to investigate genetic associations with susceptibility or resitance to T. cruzi infection and non-Chagas cardiomathy. © 2013 Deng et al.


Silveira C.,Federal University of São Paulo | Vallochi A.L.,University of Sao Paulo | Da Silva U.R.,University of Sao Paulo | Muccioli C.,Federal University of São Paulo | And 7 more authors.
British Journal of Ophthalmology | Year: 2011

Background and aims: Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients. Methods: Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA. Results: The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis. Conclusions: The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.


Luque M.C.A.,Heart Institute of Sao Paulo InCor | Luque M.C.A.,University of Sao Paulo | Gutierrez P.S.,Heart Institute of Sao Paulo InCor | Debbas V.,Heart Institute of Sao Paulo InCor | And 4 more authors.
Molecular Immunology | Year: 2015

Leukocyte migration is essential for the function of the immune system. Their recruitment from the vessels to the tissues involves sequential molecular interactions between leukocytes and endothelial cells (ECs). Many adhesion molecules involved in this process have already been described. However, additional molecules may be important in this interaction, and here we explore the potential role for CD100 and plexins in monocyte-EC binding.CD100 was shown to be involved in platelet-endothelial cell interaction, an important step in atherogenesis and thrombus formation. In a recent work we have described CD100 expression in monocytes and in macrophages and foam cells of human atherosclerotic plaques. In the present work, we have identified plexin B2 as a putative CD100 receptor in these cells. We have detected CD100 expression in the endothelium as well as in in vitro cultured endothelial cells. Blocking of CD100, plexin B1 and/or B2 in adhesion experiments have shown that both CD100 and plexins act as adhesion molecules involved in monocyte-endothelial cell binding. This effect may be mediated by CD100 expressed in both cell types, probably coupled to the receptors endothelial plexin B1 and monocytic plexin B2. These results can bring new insights about a possible biological activity of CD100 in monocyte adhesion and atherosclerosis, as well as a future candidate for targeting therapeutics. © 2015 The Authors.


Porto G.,University of Sao Paulo | Giordano R.J.,University of Houston | Giordano R.J.,University of Sao Paulo | Marti L.C.,Instituto Israelita Of Ensino E Pesquisa Albert Einstein | And 7 more authors.
PLoS ONE | Year: 2011

Thymic CD4+CD25+ cells play an important role in immune regulation and are continuously developed in the thymus as an independent lineage. How these cells are generated, what are their multiple pathways of suppressive activity and which are their specific markers are questions that remain unanswered. To identify molecules involved in the function and development of human CD4+CD25+ T regulatory cells we targeted thymic CD4+CD25+ cells by peptide phage display. A phage library containing random peptides was screened ex vivo for binding to human thymic CD4+CD25+ T cells. After four rounds of selection on CD4+CD25+ enriched populations of thymocytes, we sequenced several phage displayed peptides and selected one with identity to the Vitamin D Receptor (VDR). We confirmed the binding of the VDR phage to active Vitamin D in vitro, as well as the higher expression of VDR in CD4+CD25+ cells. We suggest that differential expression of VDR on natural Tregs may be related to the relevance of Vitamin D in function and ontogeny of these cells. © 2011 Porto et al.


Rosa D.S.,University of Sao Paulo | Rosa D.S.,Institute for Investigation in Immunology | Ribeiro S.P.,University of Sao Paulo | Ribeiro S.P.,Institute for Investigation in Immunology | And 2 more authors.
Archivum Immunologiae et Therapiae Experimentalis | Year: 2010

T cell epitope-driven vaccine design employs bioinformatic algorithms to identify potential targets of vaccines against infectious diseases or cancer. Potential epitopes can be identified with major histocompatibility complex (MHC)-binding algorithms, and the ability to bind to MHC class I or class II indicates a predominantly CD4+ or CD8+ T cell response. Furthermore, an epitope-based vaccine can circumvent evolutionary events favoring immune escape present in native proteins from pathogens. It can also focus on only the most relevant epitopes (i.e. conserved and promiscuous) recognized by the majority of the target population. Mounting evidence points to the critical role of CD4+ T cells in natural antigen encounter and active immunization. In this paper the need for CD4+ T cell help in vaccine development, the selection of CD4+ T cell epitopes for an epitope-based vaccine, and how the approach can be used to induce a protective effect are reviewed. © 2010 L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland.


Barsotti N.S.,University of Sao Paulo | Almeida R.R.,University of Sao Paulo | Costa P.R.,University of Sao Paulo | Barros M.T.,Institute for Investigation in Immunology | And 4 more authors.
PLoS ONE | Year: 2016

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. IL-10 production by sorted B cells culture and plasma sCD14 were determined by ELISA. We found that CVID patients presented decreased frequency of IL-10-producing CD24hi CD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24 CD24ihCD27 + B cells stimulated with CpG+PIB. Moreover, we found that CVID patients presented lower secretion of IL-10 by sorting-purified B cells when compared to healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals. © 2016 Barsotti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cunha-Neto E.,University of Sao Paulo | Cunha-Neto E.,Institute for Investigation in Immunology | Teixeira P.C.,University of Sao Paulo | Teixeira P.C.,Institute for Investigation in Immunology | And 6 more authors.
Autoimmunity Reviews | Year: 2011

One third of the 16. million of individuals infected by the protozoan Trypanosoma cruzi in Latin America eventually develop chronic Chagas' disease cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy with shorter survival than non-inflammatory cardiomyopathies. The presence of a T cell-rich mononuclear inflammatory infiltrate and the relative scarcity of parasites in the heart suggested that chronic inflammation secondary to the autoimmune recognition of cardiac proteins could be a major pathogenetic mechanism. Sera from CCC patients crossreactively recognize cardiac myosin and T. cruzi protein B13. T cell clones elicited from peripheral blood with T. cruzi B13 protein or its peptides could crossreactively recognize epitopes from cardiac myosin heavy chain. Likewise, CD4+ T cell clones infiltrating CCC myocardium crossreactively recognize cardiac myosin and T. cruzi protein B13, and intralesional T cell lines produce the inflammatory cytokines IFN-γ and TNF-α; Conversely, IFN-γ-induced genes and chemokines were found to be upregulated in CCC heart samples, and IFN-γ is able to induce cardiomyocyte expression of atrial natriuretic factor, a key member of the hypertrophy/heart failure signature. Proteomic analysis of CCC heart tissue showed reduced expression of the energy metabolism enzymes. It can be hypothesized that cytokine-induced modulation of cardiomyocyte gene/protein expression may be a novel disease mechanism in CCC, in addition to direct inflammatory damage. © 2010 Elsevier B.V.


Guilherme L.,University of Sao Paulo | Guilherme L.,Institute for Investigation in Immunology | Guilherme L.,Instituto Do Coracao HC FMUSP | Ferreira F.M.,University of Sao Paulo | And 7 more authors.
American Journal of Cardiovascular Drugs | Year: 2013

Streptococcus pyogenes causes severe, invasive infections such as the sequelae associated with acute rheumatic fever, rheumatic heart disease, acute glomerulonephritis, uncomplicated pharyngitis, and pyoderma. Efforts to produce a vaccine against S. pyogenes began several decades ago, and different models have been proposed. We have developed a vaccine candidate peptide, StreptInCor, comprising 55 amino acid residues of the C-terminal portion of the M protein and encompassing both the T- and B-cell protective epitopes. The present article summarizes data from the previous 5 years during which we tested the immunogenicity and safety of StreptInCor in different animal models. We showed that StreptInCor overlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules. These results are consistent with peptides that have a universal vaccine epitope. The tridimensional molecular structure of StreptInCor was elucidated by nuclear magnetic resonance spectroscopy, which showed that its structure is composed of two microdomains linked by an 18-residue α-helix. Additionally, we comprehensively evaluated the structural stability of the StreptInCor peptide in different physicochemical conditions using circular dichroism. Additional experiments were performed with inbred, outbred, and HLA class II transgenic mice. Analysis of several organs of these mice showed neither deleterious nor autoimmune reactions even after a long period of vaccination, indicating that the StreptInCor candidate peptide could be considered as an immunogenic and safe vaccine. © 2013 Springer International Publishing Switzerland.

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