Maria Almeida

Persistent abnormalities in peripheral blood dendritic cells and monocytes from HIV-1-positive patients after 1 year of antiretroviral therapy.

Summary: Antiretroviral therapy (ART) has led to marked decreases in morbidity and mortality rates among HIV-1-positive patients; however, immune recovery is not complete. Although dendritic cells (DCs) were shown to be involved in HIV-1 pathogenesis, few studies have investigated the effect of ART on DCs. We have analyzed the effect of ART on numerical distribution, expression of chemokine receptors, and ex vivo production of inflammatory cytokines by peripheral blood (PB) monocytes and DCs in a cohort of chronically infected HIV-1-positive patients. Patients were tested before therapy and at weeks +2, +4, +8, +12, and +52 after starting ART. Our results show an incomplete T-cell immune reconstitution in chronically infected patients who had undetectable plasma viremia while taking ART for 1 year. This was associated with persistent abnormalities at week +52 of ART, corresponding to increased numbers of CD16+ DCs and monocytes, as well as altered expression of CXC chemokine receptors, in the form of increased CXCR1 expression on monocytes and decreased reactivity for CXCR2 and/or CXCR4 on myeloid and plasmacytoid DCs. In addition, an abnormally high spontaneous ex vivo secretion of inflammatory cytokines by CD16+ DCs and monocytes was still detected after 1 year of ART. These abnormalities were especially pronounced in patients with less than 200 CD4+ T cells/&mgr;L, which could be related to the persistence of undetected viral replication and sustained immune activation.

Relationship between CD38 expression on peripheral blood T-cells and monocytes, and response to antiretroviral therapy: a one-year longitudinal study of a cohort of chronically infected ART-naive HIV-1+ patients.

HIV‐1 infection has been associated with high expression of CD38 on peripheral blood (PB) CD8+ and CD4+ T‐cells, which has been related with poor prognosis in untreated HIV‐1+ patients. In turn, CD38 expression on PB monocytes from HIV‐1+ individuals and its behavior after starting antiretroviral therapy (ART) have been poorly studied.

Abnormal cytokine production by circulating monocytes and dendritic cells of myeloid origin in ART-treated HIV-1+ patients relates to CD4+ T-cell recovery and HCV co-infection.

HIV-1 infection is associated with dysregulation of cytokine production by peripheral blood (PB) monocytes and dendritic cells (DC), but controversial results have been reported. We aimed to analyze the effect of antiretroviral therapy (ART) on the in vitro production of inflammatory cytokines by PB-stimulated monocytes and DC of myeloid origin -CD33(high+ ) myeloid DC (mDC) and CD33(+)/CD14(-/dim+)/CD16(high+) DC- from HIV-1+ patients and its relationship with CD4+ T-cell recovery and co-infection with hepatitis C virus (HCV). In vitro cytokine production was analyzed at the single cell level in 32 HIV-1+ patients, grouped according to the number of CD4+ T-cells/microl in PB (<200 CD4 versus >200 CD4). Patients were tested prior to therapy and at weeks +2, +4, +8, +12 and +52 after ART. Prior to ART, production of IL-6, TNF-alpha and IL-12 by mDC and of IL-8 and IL-12 by CD16+ DC was significantly increased among >200 CD4 patients. After one year of ART, increased production of IL-8 by monocytes, of TNF-alpha by mDC and of IL-1beta, IL-6 and TNF-alpha by CD16+ DC was specifically observed among <200 CD4 HIV-1+ individuals showing a high recovery of PB CD4+ T-cell counts. In turn, we found that the significantly reduced percentage of IL-1beta, IL-6, IL-8 and TNF-alpha-producing monocytes and of IL-6 and IL-8-producing mDC and CD16+ DC, as well as the significantly diminished mean amount of IL-6 produced per monocyte, mDC and CD16+ DC and of IL-12 produced per CD16+ DC observed at week +52 for the >200 CD4 patients, were related to the presence of co-infection with HCV. In summary, HIV-1+ individuals show abnormal production of inflammatory cytokines by PB-stimulated monocytes and DC of myeloid origin even after one year of ART, such abnormalities being associated with the degree of recovery of PB CD4+ T-cell counts in more immunocompromised patients and HCV co-infection in more immunocompetent HIV-1+ individuals.

Persistence of androgenic effects on the production of proinflammatory cytokines by circulating antigen-presenting cells after withdrawal of testosterone treatment in aging type 2 diabetic men with partial androgen deficiency

OBJECTIVE To test the hypothesis that T treatment withdrawal could be associated with an enhancement of proinflammatory cytokine production by peripheral blood monocytes and dendritic cells. DESIGN A prospective intervention study. SETTING Tertiary university hospital. PATIENT(S) Thirteen type 2 diabetic men aged >55 years with partial androgen deficiency and eight age-matched healthy men (controls). INTERVENTION(S) Analyses were performed before and 12 months after T replacement therapy and the results compared with those obtained for the same patients after a 3-month T withdrawal period. MAIN OUTCOME MEASURE(S) Distribution of circulating T, B, and natural killer lymphocytes, monocytes, and CD33(hi) myeloid, CD16+, and plasmacytoid dendritic cell subsets. Spontaneous and stimulated ex vivo production of inflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) by circulating monocytes and dendritic cells, which represent the most potent antigen-presenting cells. RESULT(S) The reduction or complete abrogation of spontaneous ex vivo production of proinflammatory cytokines by monocytes and dendritic cells observed after 12 months of T replacement therapy was maintained 3 months after T withdrawal. CONCLUSION(S) These are the first results showing that exogenous T treatment deprivation is not associated with an immunologic enhancement of proinflammatory cytokine production by antigen-presenting cells.

Enhanced immunological response by dendritic cells in male hypogonadism.

Eur J Clin Invest 2012; 42 (11): 1205–1212

CD38 on peripheral blood cells: The value of measuring CD38 expression on CD8 T-cells in patients receiving highly active anti-retroviral therapy

Abstract As in other viral infections, human immunodeficiency virus type 1 (HIV-1) induces an immune response, which translates into an increased lymphoid activation, despite CD4+ T-cell depletion. Such activation of the immune system is reflected not only by increased production of cytokines and other soluble factors, but also by modulation of the expression of T-cell activation-associated antigens, such as CD38, usually increasing their levels on the cell membrane. Since the first report showing that CD38 levels on CD8+ PB T-cells increase in subjects infected with the HIV-1, several studies have shown that such increased CD38 expression is a strong predictive marker for disease progression in HIV-1 infection. The levels of CD8+CD38+ T-cells not only predict progression of HIV-1 disease toward acquired immunodeficiency syndrome (AIDS) and death, but also offer additional independent predictive value to that of CD4 counts. In recent years, the introduction of highly active anti-retroviral therapy (HAART) has led to the suppression of HIV-1 replication with a dramatic decrease in plasma viral load levels in many HIV-1 infected subjects. However, success of HAART-based treatment is not achieved in all patients. Therefore, a need exists for adequate prognostic markers capable of predicting, in advance or in an early phase of treatment, lack of response to HAART. Also in this area, the measurement of CD8+CD38+ T-cells has been proposed as a useful tool for monitoring HIV-1 positive patients, given that an increased expression of CD38 on CD8+ PB T-cells could be an early marker of either viral replication or HAART failure.

Prognostic stratification of adult primary glioblastoma multiforme patients based on their tumor gene amplification profiles

Several classification systems have been proposed to address genomic heterogeneity of glioblastoma multiforme, but they either showed limited prognostic value and/or are difficult to implement in routine diagnostics. Here we propose a prognostic stratification model for these primary tumors based on tumor gene amplification profiles, that might be easily implemented in routine diagnostics, and potentially improve the patients management. Gene amplification profiles were prospectively evaluated in 80 primary glioblastoma multiforme tumors using single-nucleotide polymorphism arrays and the results obtained validated in publicly available data from 267/347 cases. Gene amplification was detected in 45% of patients, and chromosome 7p11.2 including the EGFR gene, was the most frequently amplified chromosomal region – either alone (18%) or in combination with amplification of DNA sequences in other chromosomal regions (10% of cases). Other frequently amplified DNA sequences included regions in chromosomes 12q(10%), 4q12(7%) and 1q32.1(4%). Based on their gene amplification profiles, glioblastomas were subdivided into: i) tumors with no gene amplification (55%); ii) tumors with chromosome 7p/EGFR gene amplification (with or without amplification of other chromosomal regions) (38%); and iii) glioblastoma multiforme with a single (11%) or multiple (6%) amplified DNA sequences in chromosomal regions other than chromosome 7p. From the prognostic point of view, these amplification profiles showed a significant impact on overall survival of glioblastoma multiforme patients (p>0.001). Based on these gene amplification profiles, a risk-stratification scoring system was built for prognostic stratification of glioblastoma which might be easily implemented in routine diagnostics, and potentially contribute to improved patient management.

Contents Vol. 81, 2014

Basel • Freiburg • Paris • London • New York • Chennai • New Delhi • Bangkok • Beijing • Shanghai • Tokyo • Kuala Lumpur • Singapore • Sydney Founded 1938 as ‘Schweizerische Zeitschrift für allgemeine Pathologie und Bakteriologie’ by A. v. Albertini, A. Grumbach and H. Mooser, continued as ‘Pathologia et Microbiologia’ (1960–1975) and ‘Experimental Cell Biology’ (1976–1989); incorporating ‘Pathology and Immunopathology Research’, founded 1982 as ‘Survey and Synthesis of Pathology Research’ by J.M. Cruse and R.E. Lewis, continued as ‘Pathobiology’, edited by J.M. Cruse and R.E. Lewis (1990–1998) Continued by Ch. Wittekind (1999–2004)