CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients

Sepse neonatal precoce: níveis de citocinas no sangue de cordão umbilical no diagnóstico e durante o tratamento

OBJETIVO: Avaliar parâmetros clínicos, laboratoriais e citocinas séricas em 55 neonatos que desenvolveram sepse precoce. MÉTODOS: Avaliamos os parâmetros clínicos dos neonatos relacionados com sepse precoce. No dia do diagnóstico de sepse e 48 horas após, foram realizados o leucograma diferencial e a dosagem de proteína C reativa e glicemia. As citocinas IL-1β, IL-10, IL-6 e TNF-α foram determinadas no sangue do cordão, no dia do diagnóstico de sepse, 48 e 96 horas após o início do tratamento. RESULTADOS: O tempo de internação dos neonatos foi inversamente proporcional ao peso no nascimento. Os parâmetros clínicos foram variados, especialmente a temperatura corpórea. Alterações de glicemia foram frequentes, principalmente a hipoglicemia. A alteração de hemograma mais prevalente foi a leucopenia, devido principalmente à neutropenia. Os níveis de proteína C reativa se mostraram correlacionados com o índice neutrofílico. Observamos uma correlação positiva entre os níveis de TNF-α e IL-10 entre o curso da sepse precoce e os níveis observados no cordão umbilical. CONCLUSÕES: As alterações clínicas e laboratoriais entre os neonatos com sepse são variadas. Neonatos que apresentam elevações no padrão de citocinas no momento do parto permanecem com seus níveis elevados durante o processo infeccioso

T Cell Activation and Proinflammatory Cytokine Production in Clinically Cured Tuberculosis Are Time-Dependent and Accompanied by Upregulation of IL-10.

Th1 cytokines are essential for the control of M. tuberculosis infection. The role of IL-10 in tuberculosis is controversial and there is an increasing body of evidence suggesting that the relationship between Th1 cytokines and IL-10 is not as antagonistic as it was first believed, and that these cytokines may complement each other in infectious diseases.The present study evaluated the activating capacity of CD4+ and CD8+ T cell repertoire in response to antigen stimulation through the expression of CD69 using Flow Cytometry, as well as the functionality of PBMCs by determining the cytokine profile in patients with active tuberculosis and in clinically cured patients after in vitro stimulation using ELISA. Treated patients were subdivided according to time after clinical cure (<12 months or >12 months post-treatment).We observed that T cell activation was higher in TB-treated patients, especially CD8+ T cell activation in TB-Treated >1 year. Th1 cytokines were significantly higher in TB-Treated, and the levels of IFN-γ and TNF-α increased continuously after clinical cure. Moreover, IL-10 production was significantly higher in cured patients and it was also enhanced in cured patients over time after treatment. Th17, Th2 and Th22 cytokines showed no statistically significant differences between Healthy Donors, Active-TB and TB-Treated.This study describes a scenario in which potentiation of CD4+ and CD8+ T cell activation and increased Th1 cytokine production are associated with the clinical cure of tuberculosis in the absence of significant changes in Th2 cytokine production and is accompanied by increased production of IL-10. In contrast to other infections with intracellular microorganisms, this response occurs later after the end of treatment

Interleukin-6 and C-Reactive Protein Are Overexpressed in the Liver of Perinatal Deaths Diagnosed with Fetal Inflammatory Response Syndrome

Anatomopathologic studies have failed to define the fetal inflammatory response syndrome (FIRS) as a cause of fetal death. Here, liver fragments of perinatal autopsies were collected at a university hospital from 1990 to 2009 and classified according to the cause of death, perinatal stress, and gestational age (GA) of the fetus. IL-6, TNF-α, and C-reactive protein (CRP) expression were immunostained, respectively, with primary antibody. Cases with congenital malformation, ascending infection, and perinatal anoxia showed increased IL-6, CRP, and TNF-α, respectively. Prematures presented higher expression of IL-6 whereas term births showed higher expression of CRP. Cases classified as acute stress presented higher expression of IL-6 and TNF-α and cases with chronic stress presented higher expression of CRP. GA correlated negatively with IL-6 and positively with CRP and TNF-α. Body weight correlated negatively with IL-6 and positively with CRP and TNF-α. Despite the diagnosis of FIRS being clinical and based on serum parameters, the findings in the current study allow the inference of FIRS diagnosis in the autopsied infants, based on an in situ liver analysis of these markers

Th2, Th17 and Th22 cytokines in active and clinical cured tuberculosis.

<p>Production of IL-4, IL-13, IL-17, IL-6 and IL-22 by PBMCs from Healthy Donors, patients with active tuberculosis and clinically cured patients in unstimulated (medium only) and stimulated (4 µg/mL <i>M. bovis</i> antigen) cultures. <b>A, B, C, E, F</b>. Comparison between patients with active tuberculosis and clinically cured patients (TB-treated). <b>D</b>. Comparison between active tuberculosis and different times after clinical cure (TB-treated<1 year and TB-treated>1 year). Horizontal lines represent the median, bars represent 25–75 percentiles, and vertical lines represent 10–90 percentiles. #p<0.05 in unstimulated versus stimulated cultures (4 µg/mL <i>M. bovis</i> antigen), Wilcoxon test.</p

Correlation between IL-10 and Th1 cytokines in active and clinical cured tuberculosis.

<p>Correlation between IL-10 and IFN-γ or TNF-α levels produced by PBMCs from Healthy Donors (<b>A</b>), patients with active tuberculosis (<b>B</b>) and clinically cured patients (<b>C</b>) in stimulated cultures (4 µg/mL <i>M. bovis</i> antigen). Values of <i>p</i> and <i>r</i> determined using Spearman's correlation test.</p

T cell activation in active and clinical cured tuberculosis.

<p>Variation in the activation of helper and cytolytic T cells in Healthy Donors, patients with active tuberculosis and clinically cured patients. <b>A</b>. Schematic representation of the gating strategy and determination of Δ activation of CD69+ cells in stimulated (4 µg/mL <i>M. bovis</i> antigen) and unstimulated (medium only) cultures. From left to right, T cells were separated based on FSC and SSC patterns. These cells were divided into CD4+ and CD8+ and the expression of CD69 was evaluated. Dot plots representative of each studied group are shown. Blue dots represent the staining for CD69 in unstimulated cultures, and red dots represent the stimulated cultures. The percentage of specific antigen activation was calculated by simple subtraction of the percentage of CD69+ cells in unstimulated cultures from the percentage observed in stimulated cultures and the Δ activation for each depicted dot plot is shown. The superior panel of dot plots represents the activation in CD4+, and the inferior panel represents the activation in CD8+. Dot plots representative of a single participant are shown. <b>B, C</b>. Comparison between Healthy Donors, Active-TB patients and TB-treated patients. <b>D, E</b>. Comparison between Healthy Donors, Active-TB and different times after clinical cure (TB-treated <1 year and TB-treated >1 year). <b>F</b>. Comparisons between Healthy Donors, Active-TB patients and TB-treated patients after culture in the presence of polyclonal stimulation– 2 ug/mL PHA (Polyclonal activation was calculated by simple subtraction of the percentage of CD69+ cells in unstimulated cultures from the percentage observed in PHA-stimulated cultures). Bars represent the mean and vertical lines the standard error. <b>B, C, F</b>. *p<0.0167: ANOVA test (followed by post-hoc Bonferroni test for multiple comparisons). <b>D, E</b>. *p<0.0083: ANOVA test (followed by post-hoc Bonferroni test for multiple comparisons).</p

Cytokine plasma levels in active and clinically cured tuberculosis.

<p>Plasma levels of TNF-α, IFN-γ, IL-10, IL-4, IL-13, IL-6, IL-17, TGF-β and IL-22 in Healthy Donors, patients with active tuberculosis and clinically cured patients (<b>A–G</b>). Horizontal lines represent the median, bars represent 25–75 percentiles, and vertical lines represent 10–90 percentiles. *p<0.0167: Kruskal-Wallis test (followed by post-hoc Bonferroni/Dunn test for multiple comparisons).</p