[Globalization and health: references and resources].
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Global Health↗
Biomedical subjects
F Lemonnier
Publications and source records attributed to F Lemonnier.
Identification of HER-2/neu immunogenic epitopes presented by renal cell carcinoma and other human epithelial tumors.
HER-2/neu is a tumor-associated antigen overexpressed in a large variety of human tumors. Eight HER-2/neu peptides displaying HLA-A*0201 anchoring motifs were selected and tested for their binding affinity to HLA-A*0201 and their capacity to elicit cytotoxic T lymphocyte (CTL) responses in both HLA-A*0201 transgenic mice and in HLA-A*0201(+) healthy donors. Two high-affinity (p5 and p48) and one intermediate-affinity (p1023) peptides triggered CTL responses in both transgenic mice and humans, comparable to those observed for the well-known HER2/neu dominant peptide p369. CTL induced in transgenic mice lysed HLA-A*0201(+) RMA cells infected with recombinant HER-2/neu but not cells infected with wild-type vaccinia virus. Human CTL lysed HLA-A*0201(+) HER-2/neu(+) tumor cells of different origins (breast, colon, lung and renal cancer) irrespective of the expression levels of HER-2/neu. Importantly, primed CTL specific for these epitopes were detected in freshly isolated tumor-infiltrating lymphocytes from three renal cell carcinoma patients. Therefore, the HER-2/neu peptides p5, p48 and p1023 may be good candidates for immunotherapy of a broad spectrum of tumors, including renal cell carcinoma.
Animals↗
Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope.
The immunogenicity of the Hepatitis C virus (HCV) nonstructural protein 3 (NS3) was investigated using different DNA-based strategies and a preclinical mouse model transgenic for the HLA-A2.1 molecule. Plasmids expressing NS3 either as a wild-type protein, as a fusion with murine lysosome-associated-membrane protein-1 specific sequences, or under the control of the Semliki Forest virus replicase were evaluated in vitro and in vivo. All plasmids were shown to express the expected size protein. These 3 NS3-expressing vaccines induced overall comparable levels of CTLs when measured at different times postvaccination although mice injected with the NS3-LAMP expressing plasmid showed a particularly homogeneous and overall vigorous response (specific lysis ranged from 60% to 90 % for an E:T ratio of 33.3:1 with a mean CTL precursor frequency of 1:2.10(5) cells). Out of the four HLA-A2.1-restricted NS3 epitopes previously described in HCV infected patients (aa 1073-1081, aa 1406-1415; aa 1169-1177 and aa 1287-1296), the NS3-DNA generated CTLs were predominantly targeted at the aa 1073-1081 epitope. Peptide-based immunization showed that the mouse repertoire was intact for all epitopes tested except one (aa 1287-1296). In conclusion, the 3 NS3-DNA vaccines although based on different mode of action, shared a comparable efficacy at inducing CTL. Surprisingly, the breadth of such response was restricted to a single, major epitope.
3T3 Cells↗
Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis.
HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/beta2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.
Amino Acid Sequence↗
Standard treatment of alpha-tocopherol in Alagille patients with severe cholestasis is insufficient.
Alpha-tocopherol (alpha-T) is the most effective lipid-soluble antioxidant present in cells. We investigated the efficacy of alpha-T supplements for preventing lipid peroxidation in patients with Alagille syndrome, according to the severity of cholestasis. Patients were assigned to two groups on the basis of plasma bilirubin concentration (group I, bilirubin <100 microM; group II, bilirubin >100 microM). alpha-T concentrations were determined in plasma, in isolated lipoproteins, and in red blood cell membranes. In both groups of patients, alpha-T concentrations in plasma were similar to those in control subjects, but the distribution of alpha-T in lipoproteins was affected by the abnormal lipoprotein pattern in these patients. The efficacy of alpha-T was estimated by determining the amount of hydroperoxide produced from phosphatidylcholine and phosphatidylethanolamine (PE) molecular species owing to oxidative stress induced by lipoxygenase treatment. The concentrations of phosphatidylcholine molecular species and its corresponding hydroperoxides were significantly higher in both groups of patients. In group I, alpha-T and PE molecular species concentrations were similar to those in control subjects, but PE hydroperoxide concentrations were higher than those in the control subjects. In group II, alpha-T concentration was significantly lower and the concentrations of some PE molecular species and all PE hydroperoxides were lower than those in the control subjects. In conclusion, erythrocyte membrane alpha-T concentration was significantly lower only in patients with severe jaundice, despite alpha-T supplementation, raising the question as to whether the usual treatment was appropriate in this group.
Adolescent↗
V beta T cell repertoire of CD8+ splenocytes selected on nonpolymorphic MHC class I molecules.
In this work, we have studied the role of the MHC class Ib molecules in the selection and maintenance of CD8(+) T splenocytes. We have compared the CD8(+) T cell repertoires of wild-type, H-2K-deficient, H-2D-deficient, or double knockout C57BL/6 mice. We show that the different CD8(+) repertoires, selected either by class Ia and class Ib or by class Ib molecules only, use the various V alpha (AV) and V beta (BV) rearrangements in the same proportion and without biases in the CDR3 size distribution. Furthermore, we have estimated the size of the BV repertoire in the four different strains of mice. Interestingly, we have found that the BV repertoire size is proportional to the overall number of CD8(+) splenocytes. This observation implies that BV diversity is positively correlated with the number of CD8(+) cells, even when the number of CD8(+) splenocytes is dramatically reduced (90% in the double knockout mice).
Animals↗
HLA-A2 transgenic mouse model: potential utility for development of an HCV vaccine.
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Animals↗
Persistence of memory CD8 T cells in MHC class I-deficient mice.
An understanding of how T cell memory is maintained is crucial for the rational design of vaccines. Memory T cells were shown to persist indefinitely in major histocompatibility complex (MHC) class I-deficient mice and retained the ability to make rapid cytokine responses upon reencounter with antigen. In addition, memory CD8 T cells, unlike naïve cells, divided without MHC-T cell receptor interactions. This "homeostatic" proliferation is likely to be important in maintaining memory T cell numbers in the periphery. Thus, after naïve CD8 T cells differentiate into memory cells, they evolve an MHC class I-independent "life-style" and do not require further stimulation with specific or cross-reactive antigen for their maintenance.
Adoptive Transfer↗
An invariant T cell receptor alpha chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted alpha/beta T cell subpopulation in mammals.
We describe here a new subset of T cells, found in humans, mice, and cattle. These cells bear a canonical T cell receptor (TCR) alpha chain containing hAV7S2 and AJ33 in humans and the homologous AV19-AJ33 in mice and cattle with a CDR3 of constant length. These T cells are CD4(-)CD8(-) double-negative (DN) T cells in the three species and also CD8alphaalpha in humans. In humans, their frequency was approximately 1/10 in DN, 1/50 in CD8alpha+, and 1/6,000 in CD4(+) lymphocytes, and they display an activated/memory phenotype (CD45RAloCD45RO+). They preferentially use hBV2S1 and hBV13 segments and have an oligoclonal Vbeta repertoire suggesting peripheral expansions. These cells were present in major histocompatibility complex (MHC) class II- and transporter associated with antigen processing (TAP)-deficient humans and mice and also in classical MHC class I- and CD1-deficient mice but were absent from beta2-microglobulin-deficient mice, indicating their probable selection by a nonclassical MHC class Ib molecule distinct from CD1. The conservation between mammalian species, the abundance, and the unique selection pattern suggest an important role for cells using this novel canonical TCR alpha chain.
Amino Acid Sequence↗
Analysis of T-cell defects in the specific immune response against acute lymphoblastic leukemia cells.
We previously showed that a specific antileukemia T-cytotoxic response is spontaneously elicited in acute lymphoblastic leukemia (ALL) patients and might contribute to host antileukemia defense, even though it is insufficient for tumor growth control. In this study, we report that multifactorial factors account for some of the acquired immune defects seen in ALL patients. In bone marrow of ALL patients, T cells do not express CD40L and CD25 markers, their apoptosis rate is increased, and a predominance of a CD4 cell subset expressing a Th2 phenotype is detected. A lack of expression of B7-1 molecules and other activation molecules is observed on all ALL blasts. These different parameters combined lead to in vivo dysfunction of T-cell proliferative and cytotoxic activity.
Apoptosis↗
Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia.
Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense.
Amino Acid Sequence↗
Continuous glucose monitoring in the free-moving rat.
The aim of this work was to set up an experimental model of glycemic fluctuations for assessing in the conscious freely moving rat, the performance of a continuous glucose-monitoring system, using a pocket-calculator-size electronic control unit and a miniaturized subcutaneous glucose sensor. The well-known triphasic glycemic pattern following streptozotocin injection (initial peak and secondary hypoglycemia preceding the establishment of permanent hyperglycemia) was used as a way to obtain spontaneous changes in blood glucose level over a wide concentration range. This report demonstrates that streptozotocin injection produced highly reproducible changes in the current generated by the sensor: an initial peak and a secondary nadir, during which blood sampling provided the evidence of hyperglycemia associated with immunoreactive hypoinsulinemia, and of hypoglycemia associated with hyperinsulinemia, respectively. This reproducible experimental model should be valuable for the assessment of a continuous glucose-monitoring system.
Animals↗
Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observation in blood.
The development of a hypoglycemic alarm system using a subcutaneous glucose sensor implies that a decrease in blood glucose is rapidly followed by a decrease in the signal generated by the sensor. In a first set of experiments the linearity and the kinetics of the response of sensors implanted in the subcutaneous tissue of normal rats were investigated during a progressive increase in plasma glucose concentration: the sensitivities determined between 5 and 10 mM and between 10 and 15 mM were not significantly different, and a 5-10 min delay in the sensor's response was observed. In a second set of experiments, performed in diabetic rats, the kinetics of the decrease in subcutaneous glucose concentration following insulin administration was monitored during a decrease in plasma glucose level, from 15 to 3 mmol/L. During the 20 first min following insulin administration, the sensor monitored glucose concentration in subcutaneous tissue with no lag time. Subsequently, the decrease in the estimation of subcutaneous glucose concentration preceded that of plasma glucose. This phenomenon was not observed when the same sensors were investigated in vitro during a similar decrease in glucose concentration and may be due to a mechanism occurring in vivo, such as the effect of insulin on glucose transfer from the interstitial space to the cells surrounding the sensor. It reinforces the interest of the use of implantable glucose sensors as a part of a hypoglycemic alarm.
Scintillation Counting↗
Hydroperoxides of erythrocyte phospholipid molecular species formed by lipoxygenase correlate with alpha-tocopherol levels.
The hydroperoxides corresponding to the main molecular species of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were determined after lipoxygenase treatment of erythrocyte membranes from healthy children. This work was a preliminary study prior to applying this analytical procedure to erythrocyte membranes from children with diseases associated with vitamin E deficiency. The total molecular species corresponding to 20:4 and 22:6 associated with 16:0 and 18:0 were significantly higher in PE (26.94 +/- 4.70 nmol/mg protein) than in PC (20.14 +/- 6.70 nmol/mg protein); these concentrations represented 63% of the total molecular species in PE and 22% in PC. However, the concentrations of hydroperoxides produced from these polyunsaturated fatty acid molecular species were in the same order of magnitude in PC (3.98 +/- 1.56 nmol/mg protein) and in PE (3.61 +/- 1.63 nmol/mg protein). In contrast, the molecular species concentrations containing two double bonds, such as 16:0/18:2 and 18:0/18:2 and their corresponding hydroperoxides, were clearly more elevated in PC than in PE. There was a positive relationship between the concentrations of alpha-tocopherol and each hydroperoxide of PC and PE, and this association was particularly strong in PE (P < or = 0.0001). These results suggest that alpha-tocopherol exerts a stabilizing effect toward hydroperoxides, limiting their further degradation into peroxyl radicals. The protective effect of alpha-tocopherol could be more effective in PE because more polyunsaturated fatty acids were present.
Child, Preschool↗
Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein.
Like other pathogenic viruses, HIV-1 down-modulates surface expression of major histocompatibility complex class I (MHC-I) molecules in infected cells, thus impairing lysis by cytotoxic T lymphocytes. We have observed that this phenomenon depends on the expression of Nef. nef is an early gene of primate lentiviruses, which is necessary for maintaining high virus loads and inducing AIDS. Nef is not necessary for viral replication in vitro and stimulates the endocytosis of CD4. We show that the expression of MHC-I at the surface of lymphoid, monocytic and epithelial cells was reduced in the presence of Nef protein from various HIV-1 strains. Whereas MHC-I protein synthesis and transport through the endoplasmic reticulum and cis Golgi apparatus occurred normally in Nef(+) cells, surface MHC-I molecules were rapidly internalized, accumulated in endosomal vesicles and were degraded. The stimulation of MHC-I endocytosis by Nef represents a previously undocumented viral mechanism for evading the immune response.
Cell Line↗
Fatty acid content in lymphocytes from children with syndromic paucity of interlobular bile ducts, Alagille syndrome.
Fatty acid (FA) concentrations were studied in lymphocytes isolated from children with syndromic paucity of interlobular bile ducts (PILBD), Alagille syndrome. The aim of this study was to assess whether the specific FA changes previously observed in fibroblast cultures from such patients were also present in other tissues. Lymphocyte FA, obtained both from controls and patients were studied under two experimental conditions, either after separation of the mononuclear cells or after 48 hours of culture. Freshly isolated lymphocytes from patients presented few FA changes compared to the controls. However, when patient lymphocytes were placed in culture medium for 48 hours, FA changes were amplified compared to those observed in controls; the decrease in the sum of saturated and n-6 polyunsaturated FA of total lipids was significant only in patients, and the n-3 FA of phospholipids was strikingly increased in patients (p < or = 0.001), compared to controls. These results are related to those previously observed in fibroblast cultures and suggest that placing cells in culture could reveal a pre-existing cellular abnormality in patients with PILBD.
Adolescent↗
Reduction of acetaminophen interference in glucose sensors by a composite Nafion membrane: demonstration in rats and man.
Amperometric glucose sensors typically monitor the production of hydrogen peroxide generated in the course of the enzymatic oxidation of glucose. At the applied potential necessary to oxidize the peroxide produced, other species are also electroactive and contribute to the signal. Interference of ascorbate or urate has been effectively eliminated, but that resulting from the widely used analgesic acetaminophen is not. The aim of this work was to reduce this interference, which was found to be possible by introducing a membrane constructed of Nafion. We compared the in vitro sensitivity to acetaminophen of five Nafion sensors with that of five non-Nafion sensors with identical glucose sensitivity (2.0 +/- 0.4 vs 1.9 +/- 0.1 nA.mmol-1.l-1, NS): sensitivity to acetaminophen was 12.2 +/- 2.7 vs 30.8 +/- 6.3 nA.mmol-1.l-1, respectively (p < 0.05). These sensors were tested in rats by implanting in each animal one Nafion and one non-Nafion sensors. The in vivo sensitivity to glucose was similar (0.33 +/- 0.09 vs 0.30 +/- 0.05 nA.mmol-1.l-1, NS). The current generated by an acetaminophen infusion (plasma acetaminophen plateau = 140 +/- 10 mumol/l) was much decreased in the case of the Nafion sensor: 0.5 +/- 0.3 vs 2.0 +/- 0.7 nA, p < 0.05). Five Nafion sensors were implanted in the subcutaneous tissue of normal human volunteers who were given on oral dose of 500 mg acetaminophen.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
A glucose monitoring system for on line estimation in man of blood glucose concentration using a miniaturized glucose sensor implanted in the subcutaneous tissue and a wearable control unit.
We have developed a miniaturized glucose sensor which has been shown previously to function adequately when implanted in the subcutaneous tissue of rats and dogs. Following a glucose load, the sensor output increases, making it possible to calculate a sensitivity coefficient to glucose in vivo, and an extrapolated background current in the absence of glucose. These parameters are used for estimating at any time the apparent subcutaneous glucose concentration from the current. In the previous studies, this calibration was performed a posteriori, on the basis of the retrospective analysis of the changes in blood glucose and in the current generated by the sensor. However, for clinical application of the system, an on line estimation of glucose concentration would be necessary. Thus, this study was undertaken in order to assess the possibility of calibrating the sensor in real time, using a novel calibration procedure and a monitoring unit which was specifically designed for this purpose. This electronic device is able to measure, to filter and to store the current. During an oral glucose challenge, when a stable current is reached, it is possible to feed the unit with two different values of blood glucose and their corresponding times. The unit calculates the in vivo parameters, transforms every single value of current into an estimation of the glucose concentration, and then displays this estimation. In this study, 11 sensors were investigated of which two did not respond to glucose. In the other nine trials, the volunteers were asked to record every 30 s what appeared on the display during the secondary decrease in blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗