functional-characterization-regulatory-macrophages-that-inhibit-graft

Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity

Macrophage accumulation in transplanted organs has long been recognized as a feature of allograft rejection1. Immunogenic monocytes infiltrate the ...

Icahn School of Medicine at Mount Sinai

Instituto de Salud Carlos III

Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL-2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM-CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL-4, IL-10, or IFN-gamma by PHA-activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM-CSF secretion that may be associated with chronic inflammation.

Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic.

Contamination by fasciolids takes place through ingestion of metacercariae attached to vegetables. Experimental studies were performed with plant-made foods suggesting a role in human contamination in Iran and on the usefulness of potassium permanganate as a preventive tool for killing metacercariae attached to vegetables used in salads in Egypt. In the foods assayed, although viability decreases with time, a high percentage of the metacercariae were still alive 2 and 4 weeks after preparation. Infection of laboratory animals proved that metacercariae kept their infectivity. The 5-minute tests of potassium permanganate effects showed that metacercarial viability was not affected even at the very high doses of 300, 600, and 1,200 mg/L. Careful, subsequent washing of leaves and vegetables with water is therefore needed after its application. A review on similar studies performed with metacercariae belonging to fasciolid and other trematode species affecting humans is included.

Plant-borne human contamination by fascioliasis.

A proposed mechanism for the As-induced inhibition of cell proliferation is the inhibition of IL-2 secretion. However, the effects of arsenite on IL-2 mRNA expression or on the ERK pathway in activated-T cells have not yet been described. We examined the effect of arsenite on IL-2 mRNA expression, cell activation and proliferation in PHA-stimulated murine lymphocytes. Arsenite (1 and 10 microM) decreased IL-2 mRNA expression, IL-2 secretion and cell proliferation. Arsenite (10 microM) strongly inhibited ERK-phosphorylation. However, the partial inhibition (50%) of IL-2 mRNA produced by 1 microM, consistent with the effects on IL-2 secretion and cell proliferation, could not be explained by the inhibition of ERK-phosphorylation, which was not affected at this concentration. The inhibition of IL-2 mRNA expression caused by 1 microM could be associated to effects on pathways located downstream or parallel to ERK. Arsenite also decreased early activation (surface CD69+ expression) in both CD4+ and CD8+, and decreased total CD8+ count without significantly affecting CD4+, supporting that the cellular immune response mediated by cytotoxic T cells is an arsenic target. Thus, our results suggest that arsenite decreases IL-2 mRNA levels and T-cell activation and proliferation. However, further studies on the effects of arsenite on IL-2 gene transcription and IL-2 mRNA stability are needed.

Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells.

Arsenic (As) exposure has been associated with alterations in the immune system, studies in experimental models and adults have shown that these effects involve macrophage function; however, limited information is available on what type of effects could be induced in children. The aim of this study was to evaluate effects of As exposure, through the association of inorganic As (iAs) and its metabolites [monomethylated arsenic (MMA) and dimethylated arsenic (DMA)] with basal levels of nitric oxide (NO(-)) and superoxide anion (O(2)(-)), in peripheral blood mononuclear cells (PBMC) and monocytes, and NO(-) and O(2)(-) produced by activated monocytes. Hence, a cross-sectional study was conducted in 87 children (6-10 years old) who had been environmentally exposed to As through drinking water. Levels of urinary As species (iAs, MMA and DMA) were determined by hydride generation atomic absorption spectrometry, total As (tAs) represents the sum of iAs and its species; tAs urine levels ranged from 12.3 to 1411 microg/g creatinine. Using multiple linear regression models, iAs presented a positive and statistical association with basal NO(-) in PBMC (beta=0.0048, p=0.049) and monocytes (beta=0.0044, p=0.044), while basal O(2)(-) had a significant positive association with DMA (beta=0.0025, p=0.046). In activated monocytes, O(2)(-) showed a statistical and positive association with iAs (beta=0.0108, p=0.023), MMA (beta=0.0066, p=0.022), DMA (beta=0.0018, p=0.015), and tAs (beta=0.0013, p=0.015). We conclude that As exposure in the studied children was positively associated with basal levels of NO(-) and O(2)(-) in PBMC and monocytes, suggesting that As induces oxidative stress in circulating blood cells. Additionally, this study showed a positive association of O(2)(-) production with iAs and its metabolites in stimulated monocytes, supporting previous data that suggests that these cells, and particularly the O(2)(-) activation pathway, are relevant targets for As toxicity.

Arsenic alters monocyte superoxide anion and nitric oxide production in environmentally exposed children.

Epidemiological surveillance of influenza, a disease associated with high mortality in the elderly and individuals' belonging to risk groups, is essential for the characterization of influenza epidemics as well as for the monitoring of outbreaks and the emergence of viral strains resistant to antivirals.

[National Influenza Surveillance Programme: results of influenza activity in Portugal in the 2010/2011 season].

In recent years several reports of influenza vaccine effectiveness (VE) have been made early for public health decision. The majority of these studies use the case test-negative control design (TND), which has been showed to provide, under certain conditions, unbiased estimates of influenza VE. Nevertheless, discussions have been taken on the best influenza negative control group to use. The present study aims to contribute to the knowledge on this field by comparing influenza VE estimates using three test-negative controls: all influenza negative, non-influenza respiratory virus and pan-negative.

Estimates of 2012/13 influenza vaccine effectiveness using the case test-negative control design with different influenza negative control groups.

This article reviews the historical and scientific findings of the Botanic Mission to Mozambique (1942-1948) under the Tropical Botanic Garden of the Instituto de Investigação Científica Tropical, in Lisbon, highlighting the collectors' field notes with the aim of identifying the traditional medicinal uses of Mozambican flora. Having collated information on 71 taxa (70 species and one genus), the medicinal usage of 34 species presumably not yet reported in Mozambique was identified, including five whose therapeutic use still had not yet been described in the African continent. Overall, 58 uses presumably not yet reported in Mozambique were recorded.

The Botanic Mission to Mozambique (1942-1948): contributions to knowledge of the medicinal flora of Mozambique.

Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.

DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance.

Myeloid-derived suppressor cells (MDSC) are cells of myeloid origin with enhanced suppressive function. They are negative regulators of the immune responses and comprise a heterogeneous mixture of immunosuppressive cells of monocytic (M-MDSC) and granulocytic (G-MDSC) origin. A more recent nomenclature proposes the term "suppressive monocyte derived cells" (suppressive MCs) to define CSF1/CSF2-dependent mouse suppressor cells that develop from common monocyte progenitors (cMoPs) after birth. Here, we review the literature about monocytic-derived cells with demonstrated suppressor function in vitro and in vivo within the context of solid organ transplantation.

Monocyte-Derived Suppressor Cells in Transplantation.

Recent studies suggest an association between the Interferon Inducible Transmembrane 3 (IFITM3) rs12252 variant and the course of influenza infection. However, it is not clear whether the reported association relates to influenza infection severity. The aim of this study was to estimate the hospitalization risk associated with this variant in Influenza Like Illness (ILI) patients during the H1N1 pandemic influenza.

Hospitalization Risk Due to Respiratory Illness Associated with Genetic Variation at IFITM3 in Patients with Influenza A(H1N1)pdm09 Infection: A Case-Control Study.

Immune profile for influenza viruses is highly changeable over time. Serological studies can assess the prevalence of influenza, estimate the risk of infection, highlight asymptomatic infection rate and can also provide data on vaccine coverage. The aims of the study were to evaluate pre-existing cross-protection against influenza A(H3) drift viruses and to assess influenza immunity in the Portuguese population.

Article	Year
Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. FASEB journal : official publication of the Federation of American Societies for Experimental Biology\| PubMed ID: 16461332	2006
Plant-borne human contamination by fascioliasis. The American journal of tropical medicine and hygiene\| PubMed ID: 16896136	2006
Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells. Archives of toxicology\| PubMed ID: 17009048	2007
Arsenic alters monocyte superoxide anion and nitric oxide production in environmentally exposed children. Toxicology and applied pharmacology\| PubMed ID: 20226805	2010
[National Influenza Surveillance Programme: results of influenza activity in Portugal in the 2010/2011 season]. Acta medica portuguesa\| PubMed ID: 23211197	2012
Estimates of 2012/13 influenza vaccine effectiveness using the case test-negative control design with different influenza negative control groups. Vaccine\| PubMed ID: 24962756	2014
The Botanic Mission to Mozambique (1942-1948): contributions to knowledge of the medicinal flora of Mozambique. Historia, ciencias, saude--Manguinhos\| PubMed ID: 25055327	2014
DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance. Immunity\| PubMed ID: 26070485	2015
Monocyte-Derived Suppressor Cells in Transplantation. Current transplantation reports\| PubMed ID: 26301174	2015
Hospitalization Risk Due to Respiratory Illness Associated with Genetic Variation at IFITM3 in Patients with Influenza A(H1N1)pdm09 Infection: A Case-Control Study. PloS one\| PubMed ID: 27351739	2016
Cross-protection to new drifted influenza A(H3) viruses and prevalence of protective antibodies to seasonal influenza, during 2014 in Portugal. Vaccine\| PubMed ID: 28318771	2017

Patricia Conde

Biography

JoVE Journal Publications

Other Publications