Engineered nanomaterial applications in perinatal therapeutics.

Engineered nanomaterials (ENM) are widely used in commercial, domestic, and more recently biomedical applications. While the majority of exposures to ENM are unintentional, biomedical platforms are being evaluated for use in individualized and/or tissue-targeted therapies. Treatments are often avoided during prenatal periods to reduce adverse effects on the developing fetus. The placenta is central to maternal-fetal medicine. Perturbation of placental functions can limit transfer of necessary nutrients, alter production of hormones needed during pregnancy, or allow undesired passage of xenobiotics to the developing fetus. The development of therapeutics to target specific maternal, placental, or fetal tissues would be especially important to reduce or circumvent toxicities. Therefore, this review will discuss the potential use of ENM in perinatal medicine, the applicable physiochemical properties of ENM in therapeutic use, and current methodologies of ENM testing in perinatal medicine, and identify maternal, fetal, and offspring concerns associated with ENM exposure during gestation. As potential nanoparticle-based therapies continue to develop, so does the need for thorough consideration and evaluation for use in perinatal medicine.

The effects of resistance exercise training on arterial stiffness in metabolic syndrome.

PURPOSE: Arterial stiffness is a strong independent risk factor for cardiovascular disease and is elevated in individuals with metabolic syndrome (MetS). Resistance training is a popular form of exercise that has beneficial effects on muscle mass, strength, balance and glucose control. However, it is unknown whether resistance exercise training (RT) can lower arterial stiffness in patients with MetS. Thus, the aim of this study was to examine whether a progressive RT program would improve arterial stiffness in MetS. METHODS: A total of 57 subjects (28 healthy sedentary subjects; 29 MetS) were evaluated for arterial structure and function, including pulse wave velocity (cfPWV: arterial stiffness), before and after an 8-week period of RT or continuation of sedentary lifestyle. RESULTS: We found that 8 weeks of progressive RT increased skeletal muscle strength in both Con and MetS, but did not change arterial stiffness in either MetS (cfPWV; Pre 7.9 ± 0.4 m/s vs. Post 7.7 ± 0.4 m/s) or healthy controls (cfPWV; Pre 6.9 ± 0.3 m/s vs. Post 7.0 ± 0.3 m/s). However, when cfPWV is considered as a continuous variable, high baseline measures of cfPWV tended to show a decrease in cfPWV following RT. CONCLUSION: Eight weeks of progressive RT did not decrease the group mean values of arterial stiffness in individuals with MetS or healthy controls.

Is obesity predictive of cardiovascular dysfunction independent of cardiovascular risk factors?

INTRODUCTION: Obesity is thought to exert detrimental effects on the cardiovascular (CV) system. However, this relationship is impacted by the co-occurrence of CV risk factors, type 2 diabetes (T2DM) and overt disease. We examined the relationships between obesity, assessed by body mass index (BMI) and waist circumference (WC), and CV function in 102 subjects without overt CV disease. We hypothesized that obesity would be independently predictive of CV remodeling and functional differences, especially at peak exercise. METHODS: Brachial (bSBP) and central (cSBP) systolic pressure, carotid-to-femoral pulse wave velocity (PWVcf) augmentation index (AGI; by SphygmoCor), and carotid remodeling (B-mode ultrasound) were examined at rest. Further, peak exercise cardiac imaging (Doppler ultrasound) was performed to measure the coupling between the heart and arterial system. RESULTS: In backward elimination regression models, accounting for CV risk factors, neither BMI nor WC were predictors of carotid thickness or PWVcf; rather age, triglycerides and hypertension were the main determinants. However, BMI and WC predicted carotid cross-sectional area and lumen diameter. When examining the relationship between body size and SBP, BMI (ß=0.32) and WC (ß=0.25) were predictors of bSBP (P<0.05), whereas, BMI was the only predictor of cSBP (ß=0.22, P<0.05) indicating a differential relationship between cSBP, bSBP and body size. Further, BMI (ß=-0.26) and WC (ß=-0.27) were independent predictors of AGI (P<0.05). As for resting cardiac diastolic function, WC seemed to be a better predictor than BMI. However, both BMI and WC were inversely and independently related to arterial-elastance (net arterial load) and end-systolic elastance (cardiac contractility) at rest and peak exercise. CONCLUSION: These findings illustrate that obesity, without T2DM and overt CV disease, and after accounting for CV risk factors, is susceptible to pathophysiological adaptations that may predispose individuals to an increased risk of CV events.

Long-term control of carbapenemase-producing Enterobacteriaceae at the scale of a large French multihospital institution: a nine-year experience, France, 2004 to 2012.

In 2009, following the occurrence of several outbreaks of carbapenemase-producing Enterobacteriaceae (CPE), a programme for controlling the spread of CPE was implemented in the 38 hospitals of the Assistance Publique-Hôpitaux de Paris, a 21,000-bed institution. This programme included recommendations to isolate, and screen for CPE, patients previously hospitalised abroad, and bundled measures to control cross transmission (barrier precautions, dedicated staff and screening of contact patients). From 2004 to 2012, 140 CPE index cases were identified, 17 leading to outbreaks. After application of the programme, in spite of an increase in the number of CPE index cases epidemiologically linked with a recent stay or hospitalisation abroad, the proportion of cases followed by outbreaks, which was 40% (4/10) before 2009, decreased to 10% (13/130) (p=0.02), and the proportion of secondary cases among all CPE cases decreased from 69% (22/32) to 23% (38/168), (p<0.001). The number of secondary cases varied significantly depending on the speed and strength of the measures implemented around the CPE index case: quick (within two days of patient admission at the hospital) setting of nursing staff dedicated to the patient, quick setting of simple barrier precautions, or delayed measures of control (p=0.001). A sustained and coordinated strategy can lead to control CPE at the level of a large regional multi-hospital institution in a country where CPE are at an emerging stage.

Novel scores relevant to antimicrobial resistance and hospital-acquired infections developed with data from a multi-hospital consortium in the Parisian region of France.

PURPOSE: Indicators for comparing and understanding differences in antimicrobial resistance (AMR) and healthcare-associated infections (HAIs) for benchmarking are essential to identify priorities for hospitals. METHODS: This study measured the incidence of hospital-acquired or resistant Gram-negative bacilli bloodstream infections (GNB-BSIs) in a large public healthcare consortium in the Parisian region of France. RESULTS: Within each hospital, there was a strong positive correlation between the incidence of GNB-BSIs due to resistant GNB and the incidence of hospital-acquired GNB-BSIs. Two scores measuring AMR and HAI rates by combining different GNB-BSI incidence rates were developed as indicators. These scores were highly variable within the hospital consortium. On multi-variate analysis, AMR and HAI scores were significantly associated with the proportion of surgical beds, staff absenteeism and the consumption of alcohol-based hand rub, with the latter two characteristics being amenable to interventions. Carbapenem use was also linked to AMR, but this may be because carbapenems are the preferred drug for treating resistant infections. CONCLUSION: These results shed light on the incidence of HAIs and AMR in the study hospitals, and suggest possibilities for targeted interventions at healthcare facility level.

Single pulmonary nanopolystyrene exposure in late-stage pregnancy dysregulates maternal and fetal cardiovascular function.

Large-scale production and waste of plastic materials have resulted in widespread environmental contamination by the breakdown product of bulk plastic materials to micro- and nanoplastics (MNPs). The small size of these particles enables their suspension in the air, making pulmonary exposure inevitable. Previous work has demonstrated that xenobiotic pulmonary exposure to nanoparticles during gestation leads to maternal vascular impairments, as well as cardiovascular dysfunction within the fetus. Few studies have assessed the toxicological consequences of maternal nanoplastic (NP) exposure; therefore, the objective of this study was to assess maternal and fetal health after a single maternal pulmonary exposure to polystyrene NP in late gestation. We hypothesized that this acute exposure would impair maternal and fetal cardiovascular function. Pregnant rats were exposed to nanopolystyrene on gestational day 19 via intratracheal instillation. 24 h later, maternal and fetal health outcomes were evaluated. Cardiovascular function was assessed in dams using vascular myography ex vivo and in fetuses in vivo function was measured via ultrasound. Both fetal and placental weight were reduced after maternal exposure to nanopolystyrene. Increased heart weight and vascular dysfunction in the aorta were evident in exposed dams. Maternal exposure led to vascular dysfunction in the radial artery of the uterus, a resistance vessel that controls blood flow to the fetoplacental compartment. Function of the fetal heart, fetal aorta, and umbilical artery after gestational exposure was dysregulated. Taken together, these data suggest that exposure to NPs negatively impacts maternal and fetal health, highlighting the concern of MNPs exposure on pregnancy and fetal development.

Healthcare worker protection against mpox contamination: position paper of the French Society for Hospital Hygiene.

In the context of the recent re-emergence of mpox worldwide, the French Society for Hospital Hygiene (SF2H) performed a literature review of the transmission paths and proposed specific recommendations for healthcare workers (HCWs) caring for patients with suspected or confirmed MPXV. In developed countries, the risk of contamination among HCWs in healthcare facilities seemed to be very low, limited to contamination through needle stick injuries. Two additional contamination cases were reported and not fully explained. Beyond healthcare settings, the analysis of the literature highlighted (i) a main contamination route during sexual intercourse, mainly among men who have sex with men, and (ii) a very low secondary attack rate in other contexts, such as schools or jails. Numerous studies have reported molecular or virus identification on surfaces or in the air surrounding patients, without any association with the low secondary case incidence; moreover, the minimum infectious dose through air or mucosal exposure is still unknown. Owing to the lack of evidence of MPXV respiratory transmission in the healthcare setting, the SF2H recommends the implementation of standard and contact precautions combined with medical/surgical mask use. Owing to the lack of evidence of transcutaneous contamination, the SF2H recommends the use of gloves only if contact with cutaneous lesions or mucous membranes occurs. Regarding the risk of contamination from the environment in healthcare facilities, additional studies must be conducted to investigate this.

Long-term control of vancomycin-resistant Enterococcus faecium at the scale of a large multihospital institution: a seven-year experience.

Repeated outbreaks of vancomycin-resistant Enterococcus faecium (VRE) occurred between 2004 and 2010 in Assistance Publique--Hôpitaux de Paris (AP-HP), a 23,000-bed multi-hospital institution. From August 2004 to December 2005, the French guidelines for preventing cross-transmission of multiresistant bacteria were applied. Because the number of VRE cases continued to increase, an institutional control programme was implemented from January 2006 onwards: it foresees stopping transfer of VRE and contact patients, separating VRE and contact patients in distinct cohorts, intervention of a central infection control team to support local teams, and quick application of measures as soon as first VRE cases are identified. Between August 2004 and December 2010, 45 VRE outbreaks occurred in 21 of the 38 AP-HP hospitals, comprising 533 cases. Time series analysis showed that the mean number of cases increased by 0.8 cases per month (95% confidence interval (CI): 0.3 to 1.3, p=0.001) before, and decreased by 0.7 cases per month after implementation of the programme (95% CI: -0.9 to -0.5, p<0.001), resulting in a significant trend change of -1.5 cases per month (95% CI: -2.1 to -0.9, p<0.001). The number of cases per outbreak was significantly lower after implementation of the programme. A sustained and coordinated strategy can control emerging bacteria at the level of a large regional multihospital institution.

Considering intrauterine location in a model of fetal growth restriction after maternal titanium dioxide nanoparticle inhalation.

Fetal growth restriction (FGR) is a condition with several underlying etiologies including gestational disease (e.g., preeclampsia, gestational diabetes) and xenobiotic exposure (e.g., environmental contaminants, pharmaceuticals, recreational drugs). Rodent models allow study of FGR pathogenesis. However, given the multiparous rodent pregnancy, fetal growth variability within uterine horns may arise. To ascertain whether intrauterine position is a determinant of fetal growth, we redesigned fetal weight analysis to include litter size and maternal weight. Our FGR model is produced by exposing pregnant Sprague Dawley rats to aerosolized titanium dioxide nanoparticles at 9.44 ± 0.26 mg/m3 on gestational day (GD) 4, GD 12 or GD 17 or 9.53 ± 1.01 mg/m3 between GD 4-GD 19. In this study fetal weight data was reorganized by intrauterine location [i.e., right/left uterine horn and ovarian/middle/vaginal position] and normalized by maternal weight and number of feti per uterine horn. A significant difference in fetal weight in the middle location in controls (0.061g ± 0.001 vs. 0.055g ± 0.002), GD 4 (0.033g ± 0.003 vs. 0.049g ± 0.004), and GD 17 (0.047g ± 0.002 vs. 0.038g ± 0.002) exposed animals was identified. Additionally, GD 4 exposure produced significantly smaller feti in the right uterine horn at the ovarian end (0.052g ± 0.003 vs. 0.029g ± 0.003) and middle of the right uterine horn (0.060g ± 0.001 vs. 0.033g ± 0.003). GD 17 exposure produced significantly smaller feti in the left uterine horn middle location (0.055g ± 0.002 vs. 0.033 ± 0.002). Placental weights were unaffected, and placental efficiency was reduced in the right uterine horn middle location after GD 17 exposure (5.74g ± 0.16 vs. 5.09g ± 0.14). These findings identified: 1) differences in fetal weight of controls between the right and left horns in the middle position, and 2) differential effects of single whole-body pulmonary exposure to titanium dioxide nanoparticles on fetal weight by position and window of maternal exposure. In conclusion, these results indicate that consideration for intrauterine position, maternal weight, and number of feti per horn provides a more sensitive assessment of FGR from rodent reproductive and developmental studies.

Itk negatively regulates induction of T cell proliferation by CD28 costimulation.

CD28 is a cell surface molecule that mediates a costimulatory signal crucial for T cell proliferation and lymphokine production. The signal transduction mechanisms of CD28 are not well understood. Itk, a nonreceptor protein tyrosine kinase specifically expressed in T cells and mast cells, has been implicated in the CD28 signaling pathway because of reports that it becomes phosphorylated on tyrosines and associates with CD28 upon cross-linking of the cell surface molecule. To determine whether Itk plays a functional role in CD28 signaling, we compared T cells from Itk-deficient mice and control mice for their responses to CD28 costimulation. T cells defective in Itk were found to be fully competent to respond to costimulation. Whereas the CD3-mediated proliferative response was severely compromised in the absence of Itk, the calcineurin-independent CD28-mediated response was significantly elevated when compared with cells from control animals. The augmented proliferation was not due to increased production of interleukin-2. The results suggest that Itk has distinct roles in the CD3 versus the CD28 signaling pathways. By negatively regulating the amplitude of signaling upon CD28 costimulation, Itk may provide a means for modulating the outcome of T cell activation during development and during antigen-driven immune responses.

Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4(+) T cells.

Peripheral tolerance mechanisms normally prevent delivery of T cell help to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitizes B cell antigen receptor (BCR) signaling on anergic B cells so that they are not stimulated into clonal expansion by CD4(+) T cells but instead are eliminated by Fas (CD95)-induced apoptosis. Because a range of BCR-induced signals and responses are repressed in anergic B cells, it is not known which of these are critical to regulate for Fas-mediated peripheral tolerance. Display of the costimulatory molecule, B7.2 (CD86), represents a potentially important early response to acute BCR engagement that is poorly induced by antigen on anergic B cells. We show here that restoring B7.2 expression on tolerant B cells using a constitutively expressed B7.2 transgene is sufficient to prevent Fas-mediated deletion and to trigger extensive T cell-dependent clonal expansion and autoantibody secretion in the presence of specific T cells. Dysregulated expression of B7.2 on tolerant B cells caused a more extreme reversal of peripheral tolerance than that caused by defects in Fas or Fas ligand, and resulted in T cell-dependent clonal expansion and antibody secretion comparable in magnitude to that made by foreign antigen-specific B cells. These findings demonstrate that repression of B7.2 is critical to eliminate autoreactive B cells by Fas in B cell-T cell interactions. The possible role of B7.2 dysregulation in systemic autoimmune diseases is discussed.

Control of a multi-hospital outbreak of KPC-producing Klebsiella pneumoniae type 2 in France, September to October 2009.

An outbreak of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae type 2 was detected in September 2009 in two hospitals in a suburb south of Paris, France. In total, 13 KPC-producing K. pneumoniae type 2 cases (four with infections and nine with digestive-tract colonisations) were identified, including a source case transferred from a Greek hospital. Of the 13 cases, seven were secondary cases associated with use of a contaminated duodenoscope used to examine the source case (attack rate: 41%) and five were secondary cases associated with patient-to-patient transmission in hospital. All isolated strains from the 13 patients: (i) exhibited resistance to all antibiotics except gentamicin and colistin, (ii) were more resistant to ertapenem (minimum inhibitory concentration (MIC) always greater than 4 mg/L) than to imipenem (MIC: 1­8 mg/L, depending on the isolate), (iii) carried the blaKPC-2 and blaSHV12 genes and (iv) had an indistinguishable pulsed-field gel electrophoresis (PFGE) pattern. These cases occurred in three hospitals: some were transferred to four other hospitals. Extended infection control measures implemented in the seven hospitals included: (i) limiting transfer of cases and contact patients to other wards, (ii) cohorting separately cases and contact patients, (iii) reinforcing hand hygiene and contact precautions and (iv) systematic screening of contact patients. Overall, 341 contact patients were screened. A year after the outbreak, no additional case has been identified in these seven hospitals. This outbreak emphasises the importance of rapid identification and notification of emerging highly resistant K. pneumoniae strains in order to implement reinforced control measures.

Compounding impact of severe weather events fuels marine heatwave in the coastal ocean.

Exposure to extreme events is a major concern in coastal regions where growing human populations and stressed natural ecosystems are at significant risk to such phenomena. However, the complex sequence of processes that transform an event from notable to extreme can be challenging to identify and hence, limit forecast abilities. Here, we show an extreme heat content event (i.e., a marine heatwave) in coastal waters of the northern Gulf of Mexico resulted from compounding effects of a tropical storm followed by an atmospheric heatwave. This newly identified process of generating extreme ocean temperatures occurred prior to landfall of Hurricane Michael during October of 2018 and, as critical contributor to storm intensity, likely contributed to the subsequent extreme hurricane. This pattern of compounding processes will also exacerbate other environmental problems in temperature-sensitive ecosystems (e.g., coral bleaching, hypoxia) and is expected to have expanding impacts under global warming predictions.

Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a PET study.

Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) in Parkinson's disease is thought to produce adverse events such as emotional disorders, and in a recent study, we found fear recognition to be impaired as a result. These changes have been attributed to disturbance of the STN's limbic territory and would appear to confirm that the negative emotion recognition network passes through the STN. In addition, it is now widely acknowledged that damage to the orbitofrontal cortex (OFC), especially the right side, can result in impaired recognition of facial emotions (RFE). In this context, we hypothesized that this reduced recognition of fear is correlated with modifications in the cerebral glucose metabolism of the right OFC. The objective of the present study was first, to reinforce our previous results by demonstrating reduced fear recognition in our Parkinson's disease patient group following STN DBS and, second, to correlate these emotional performances with glucose metabolism using (18)FDG-PET. The (18)FDG-PET and RFE tasks were both performed by a cohort of 13 Parkinson's disease patients 3 months before and 3 months after surgery for STN DBS. As predicted, we observed a significant reduction in fear recognition following surgery and obtained a positive correlation between these neuropsychological results and changes in glucose metabolism, especially in the right OFC. These results confirm the role of the STN as a key basal ganglia structure in limbic circuits.

Effect of Gestational Age on Maternofetal Vascular Function Following Single Maternal Engineered Nanoparticle Exposure.

Normal pregnancy outcome is accomplished, in part, by rapid and expansive physiological adaptations to the systemic circulation, the extent of which is specific to gestational day (GD) and anatomical location. Pregnancy-related hemodynamic changes in uterine placental blood flow stimulate compensatory vascular signaling and remodeling that begins early and continues throughout gestation. Exposure of the maternal environment to engineered nanomaterials (ENM) during pregnancy has been shown to impact health of the dam, fetus, and adult offspring; however, the consequences of specific temporal (gestational age) and spatial (vascular location) considerations are largely undetermined. We exposed pregnant Sprague-Dawley rats to nano-TiO2 aerosols at three critical periods of fetal development (GD 4, 12, and 17) to identify vascular perturbations associated with ENM exposure at these developmental milestones. Vascular reactivity of the maternal thoracic aorta, the uterine artery, the umbilical vein, and the fetal thoracic aorta were evaluated using wire myography on GD 20. While impairments were noted at each level of the maternofetal vascular tree and at each exposure day, our results indicate the greatest effects may be identified within the fetal vasculature (umbilical vein and fetal aorta), wherein effects of a single maternal inhalational exposure to nano-TiO2 on GD 4 modified responses to cholinergic, NO, and α-adrenergic signaling.

Identification and quantification of gold engineered nanomaterials and impaired fluid transfer across the rat placenta via ex vivo perfusion.

Development and implementation of products incorporating nanoparticles are occurring at a rapid pace. These particles are widely utilized in domestic, occupational, and biomedical applications. Currently, it is unclear if pregnant women will be able to take advantage of the potential biomedical nanoproducts out of concerns associated with placental transfer and fetal interactions. We recently developed an ex vivo rat placental perfusion technique to allow for the evaluation of xenobiotic transfer and placental physiological perturbations. In this study, a segment of the uterine horn and associated placenta was isolated from pregnant (gestational day 20) Sprague-Dawley rats and placed into a modified pressure myography vessel chamber. The proximal and distal ends of the maternal uterine artery and the vessels of the umbilical cord were cannulated, secured, and perfused with physiological salt solution (PSS). The proximal uterine artery and umbilical artery were pressurized at 80 mmHg and 50 mmHg, respectively, to allow countercurrent flow through the placenta. After equilibration, a single 900 µL bolus dose of 20 nm gold engineered nanoparticles (Au-ENM) was introduced into the proximal maternal artery. Distal uterine and umbilical vein effluents were collected every 10 min for 180 min to measure placental fluid dynamics. The quantification of Au-ENM transfer was conducted via inductively coupled plasma mass spectrometry (ICP-MS). Overall, we were able to measure Au-ENM within uterine and umbilical effluent with 20 min of material infusion. This novel methodology may be widely incorporated into studies of pharmacology, toxicology, and placental physiology.

Role of pontine neurons in central O(2) chemoreflex during development in bullfrogs (Lithobates catesbeiana).

The present study used an in vitro brainstem preparation from pre-metamorphic tadpoles and adult bullfrogs (Lithobates catesbeiana) to understand the neural mechanisms associated with central O(2) chemosensitivity and its maturation. In this species, brainstem hypoxia increases fictive lung ventilation in tadpoles but decreases in adults. Previous studies have shown that alpha(1)-adrenoceptor inactivation prevents these responses, suggesting that noradrenergic neurons are involved. We first tested the hypothesis that the pons (which includes noradrenergic neurons from the locus coeruleus; LC) plays a role in the lung burst frequency response to central hypoxia by comparing the effects of brainstem transection at the LC level between pre-metamorphic tadpoles and adults. Data show that brainstem transection prevents the lung burst frequency response in both stage groups. During development, the progressive decrease in the Na(+)/K(+)/Cl(-) co-transporter NKCC1 contributes to the maturation of neural networks. Because NKCC1 becomes activated during hypoxia, we then tested the hypothesis that NKCC1 contributes to maturation of the central O(2) chemoreflex. Double labeling experiments showed that the proportion of tyrosine hydroxylase positive neurons expressing NKCC1 in the LC decreases during development. Inactivation of NKCC1 with bumetanide bath application reversed the lung burst response to hypoxia in tadpoles. Bumetanide inhibited the response in adults. These data indicate that a structure within the pons (potentially the LC) is necessary to the central hypoxic chemoreflex and demonstrate that NKCC1 plays a role in central O(2) chemosensitivity and its maturation in this species.

CD23 antigen regulation and signaling in chronic lymphocytic leukemia.

B lymphocytes from patients with chronic lymphocytic leukemia (B-CLLs), strongly express the CD23 antigen, a surface marker with significant prognostic importance in this disease. Because we previously reported that IL-4 shows a poor capacity for CD23 expression on B-CLLs, we first examined the possible mechanisms underlying CD23 overexpression on B-CLLs and found that mitogen-activated CLL T cells release soluble factors that are capable, in synergy with IL-4, of strongly inducing CD23. Using neutralizing Abs, we noticed that the T-cell-derived enhancing activity is entirely ascribed to the combined effects of IFN gamma (potent inhibitor of CD23 on normal B cells), TNF alpha (which has no effect on normal B cells), and IL-2 (which has a slight enhancing effect on both CLL and normal B cells). Furthermore, recombinant IFN gamma as well as IFN alpha, TNF alpha, and IL-2 (but not IL-3, IL-5, IL-6, IL-7, and lymphotoxin) significantly enhance CD23 protein and mRNA expression on B-CLLs, in the presence or absence of IL-4. Inasmuch as optimal CD23 expression absolutely requires the combination of IFN gamma, IL-2, TNF alpha (the production of which is increased in CLL disease), and IL-4, it was relevant to show that IL-4 mRNA is indeed expressed in fresh T-CLL cells. We next examined the possible role of CD23 in the regulation of B-CLL proliferation. Signaling through CD23 via ligation of the antigen by F(ab')2 anti-CD23 MAb but not Fab fragments inhibits the cytokine-induced B-CLL DNA synthesis. It is concluded that the CD23 gene is abnormally regulated in B-CLL disease and that cross-linking of CD23 molecule delivers a negative growth signal to the leukemic B cells.

Glucocorticoids increase the synthesis of immunoglobulin E by interleukin 4-stimulated human lymphocytes.

This study indicates that hydrocortisone (HC) markedly increases the synthesis of immunoglobulin E (IgE) by interleukin 4 (IL-4)-stimulated human lymphocytes. The effect is glucocorticoid specific and is obtained with low concentrations of HC (0.1-10 microM). In both the early and the late phase of the IL-4-induced response HC exerts its effects which are respectively IL-4 dependent and IL-4 independent. The IgE potentiation cannot be explained by the inhibition of interferon-gamma (IFN-gamma) production since it is observed in the absence of endogenous secretion of IFN-gamma. HC inhibits the production of IgE-binding factors (soluble CD23) and the expression of the low-affinity receptor for IgE, also known as the (Fc epsilon RII) CD23 antigen; however, the residual expression of Fc epsilon RII by IL-4- and HC-treated peripheral blood mononuclear cells (PBMCs) is important since the IgE response of these cells is markedly inhibited by anti-CD23 monoclonal antibody. HC acts mainly by amplifying the cellular interactions between monocytes and lymphocytes; indeed, HC has no effect on monocyte-depleted PBMCs, and moreover, monocytes cannot be replaced by soluble factors. Most importantly, T cells are not required for the induction of IgE synthesis by costimulation with IL-4 and HC. However, the IgE response of rigorously T cell-depleted PBMCs may be further increased by the addition of T cells. Further analysis of the permissive effect of HC on the synthesis of IgE by T cell-depleted PBMCs suggests that HC acts in synergy with IL-4 to trigger the activation and the differentiation of B cells into IgE-producing cells.