Development of allergy in children. I. Association with virus infections.

Children born into allergic families, with two allergic parents, are at high risk of developing allergy within the first 5 years of life. In order to observe possible external factors in the sensitization process, a prospective study of 13 such children was done, in which serial clinical and immunologic observations were made at 3- to 6-month intervals over a period of 1 to 4 yr. Eleven of these children are now clinically allergic; 5 have asthma. Immunologic evidence for allergic sensitization was observed in these 11 children by RAST, antigen-induced leukocyte histamine release, lymphoblastogenesis, and rise in serum IgE. Upper respiratory infections (URI) occurred in these 11 allergic children 1 to 2 months prior to the onset of allergic sensitization. In 10 of these 11 URI children, complement-fixing antibodies to viruses (parainfluenza, RSV, CMV) increased in the same blood samples in which immunologic allergic sensitization was first evidenced. This coincidence suggests that certain viruses may contribute to the allergic sensitization process

BPTF Enhances Chemotherapy Induced Cytotoxicity

BPTF Enhances Chemotherapy Induced Cytotoxicity Valentina Posada, Depts. of Biology, Chemistry, & Religious Studies, with Dr. Joseph Landry, Dept. of Human Molecular Genetics New chemotherapies and immunotherapy treatments have greatly improved the outcomes of many cancers. However, for Triple Negative Breast Cancer (TNBC), existing therapies are not very effective long term as the disease becomes resistant and has low immunogenicity. Here we show the early development of a new way to treat the disease by combining existing chemotherapies with depletion of the Nucleosome Remodeling Factor (NURF). NURF is an ATP-dependent chromatin remodeling complex that is over-expressed in cancers and has shown to inhibit the anti-tumor immune response. The largest and essential subunit of the complex, BPTF is required for function. BPTF shRNA-mediated knockdown (KD) was done as a way to deplete cells of NURF. Our first aim was to determine if BPTF-KD cells showed enhanced sensitization to chemotherapies most prominently Doxorubicin. The results from completing this aim showed sensitization to several chemotherapies which correlated with enhanced therapy-induced autophagy. Our second aim was then to investigate the role of autophagy in the sensitization of BPTF-KD cells to chemotherapies. Autophagy is a process by which cells undergoing stress consume their cellular components. This process is mediated in part by the ATG5 protein. ATG5 KD was done through lentivirus transfection, and in turn, functional blockade of autophagy was achieved as confirmed by Western blotting. Results showed that BPTF-KD cells did not have enhanced sensitivity to Doxorubicin through the blockade of autophagy, which suggested a non-protective role in autophagy, while the BPTF-WT cells that had autophagy blocked did show an enhanced sensitization, suggesting a cytoprotective role. Aims were then tested in vivo to determine the role of autophagy in BPTF-KD cells in vivo. BPTF-KD and ATG5-KD 4T1 cells were transplanted into mice and tumor volume over time was measured. Syngeneic mouse models showed that the BPTF-KD tumors had significantly smaller tumor volumes than the control when treated with Doxorubicin, and therefore showed sensitization to Doxorubicin. Results for the ATG5 KD mice show tumors growing better in the WT while growing worse in the KD1/ KD2 mice suggesting that autophagy is required for sensitization of BPTF-KD tumors to Doxorubicin in vivo. The third aim of the project was to determine the possible immune-modulatory consequences of treating BPTF KD cells with chemotherapies. Natural Killer (NK) cells were depleted in mice to see if there would be a change in the sensitization to therapies. Results showed that once we depleted NK cells in mice with a mAb-depletion strategy, the sensitization to Doxorubicin was lost. Furthermore, a metabolomics screening was conducted and reductions in prostaglandin E2 (PGE2) were discovered in the therapy treated BPTF-KD cells. PGE2 is a well know immune suppressive metabolite produced by tumor cells to suppress the anti-tumor immune response. Further results showed PGE2 reductions when autophagy was blocked by ATG5 KD in the BPTF-KD cells. This result could explain the improvements in tumor growth within the mice since PGE2 is a known NK cell inhibitor. Together, these results suggest that NURF could be a therapeutic target for enhancing clinical outcomes in Triple Negative Breast Cancer Patients.https://scholarscompass.vcu.edu/uresposters/1328/thumbnail.jp

Influence of the conditions of sensitization on the characteristics of p-DSCs sensitized with asymmetric squaraines

The effect of the conditions of sensitization on the photoelectrochemical performance of p-type dye-sensitized solar cells (p-DSCs) with screen-printed nickel oxide (NiO) photocathodes is analyzed. The dye-sensitizers employed in the present study are asymmetric squaraines. The conditions of sensitization differ for the relative concentration of the anti-aggregating agentCDCA(chenideoxycholic acid) with respect to the concentration of the dye-sensitizer. The co-adsorption of CDCA onto NiO electrode brings about a decrease in the surface concentration of the anchored dye as well as a blueshift of the characteristic wavelengths of optical absorption of the asymmetric squaraines considered here. Beside this, the employment of CDCA as co-adsorbent reduces the overall conversion performance of the resulting squaraine-sensitized p-DSCs with consequent diminution of the short-circuit current density. This result is ascribed to the acid action of CDCA toward the amminic nitrogen of the squaraines. Quantum efficiency spectra show that CDCA acts as a quencher of the intrinsic photoelectrochemical activity of NiO. Moreover, CDCA does not interfere with the mechanism of charge injection effectuated by the photoexcited squaraines. The photoelectrochemical impedance spectra was analyzed employing a model of equivalent circuit developed for semiconducting nanostructure electrodes

Heterologous carriers in the anamnestic antihapten response

Anamnestic antihapten responses were obtained to trinitrophenyl (TNP) when rabbits sensitized to trinitrophenyl-hemocyanin (TNP-KLH) were challenged with TNP-heterologous protein conjugates. Hapten-heterologous carrier conjugates elicited antihapten titers similar in magnitude to those elicited by the homologous carrier conjugate. Hapten-heterologous carrier recall of antihapten was successful as early as 37 days and as late as 11 months after sensitization. There was no correlation between anti-TNP-precipitating antibody titer after sensitization and the ability to respond to challenge by hapten-heterologous carrier. The results are discussed in terms of immunogenicity of sensitization, suppressive effects of persisting postsensitization antibody, and submolecular haptenic environment as factors possibly affecting the heterologous recall process

Applying the adverse outcome pathway (AOP) for food sensitization to support in vitro testing strategies

Background Before introducing proteins from new or alternative dietary sources into the market, a compressive risk assessment including food allergic sensitization should be carried out in order to ensure their safety. We have recently proposed the adverse outcome pathway (AOP) concept to structure the current mechanistic understanding of the molecular and cellular pathways evidenced to drive IgE-mediated food allergies. This AOP framework offers the biological context to collect and structure existing in vitro methods and to identify missing assays to evaluate sensitizing potential of food proteins. Scope and approach In this review, we provide a state-of-the-art overview of available in vitro approaches for assessing the sensitizing potential of food proteins, including their strengths and limitations. These approaches are structured by their potential to evaluate the molecular initiating and key events driving food sensitization. Key findings and conclusions The application of the AOP framework offers the opportunity to anchor existing testing methods to specific building blocks of the AOP for food sensitization. In general, in vitro methods evaluating mechanisms involved in the innate immune response are easier to address than assays addressing the adaptive immune response due to the low precursor frequency of allergen-specific T and B cells. Novel ex vivo culture strategies may have the potential to become useful tools for investigating the sensitizing potential of food proteins. When applied in the context of an integrated testing strategy, the described approaches may reduce, if not replace, current animal testing approaches

Role of dopamine D1-like receptors in methamphetamine locomotor responses of D2 receptor knockout mice

Behavioral sensitization to psychostimulants manifests as an increased locomotor response with repeated administration. Dopamine systems are accepted to play a fundamental role in sensitization, but the role of specific dopamine receptor subtypes has not been completely defined. This study used the combination of dopamine D2 receptor-deficient mice and a D1-like antagonist to examine dopamine D1 and D2 receptor involvement in acute and sensitized locomotor responses to methamphetamine. Absence of the dopamine D2 receptor resulted in attenuation of the acute stimulant effects of methamphetamine. Mutant and wild-type mice exhibited sensitization that lasted longer within the time period of the challenge test in the mutant animals. Pretreatment with the D1-like receptor antagonist SCH 23390 produced more potent reductions in the acute and sensitized locomotor responses to methamphetamine in D2 receptor-deficient mice than in wild-type mice; however, the expression of locomotor sensitization when challenged with methamphetamine alone was equivalently attenuated by previous treatment with SCH 23390. These data suggest that dopamine D2 receptors play a key role in the acute stimulant and sensitizing effects of methamphetamine and act in concert with D1-like receptors to influence the acquisition of methamphetamine-induced behavioral sensitization, traits that may influence continued methamphetamine use.Fil: Kelly, M. A.. Oregon Health And Science University; Estados UnidosFil: Low, M. J.. Oregon Health And Science University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Phillips, T. J.. Oregon Health And Science University; Estados Unido

An algorithm for diagnosing IgE-mediated food allergy in study participants who do not undergo food challenge.

BACKGROUND: Food allergy diagnosis in clinical studies can be challenging. Oral food challenges (OFC) are time-consuming, carry some risk and may, therefore, not be acceptable to all study participants. OBJECTIVE: To design and evaluate an algorithm for detecting IgE-mediated food allergy in clinical study participants who do not undergo OFC. METHODS: An algorithm for trial participants in the Barrier Enhancement for Eczema Prevention (BEEP) study who were unwilling or unable to attend OFC was developed. BEEP is a pragmatic, multi-centre, randomized-controlled trial of daily emollient for the first year of life for primary prevention of eczema and food allergy in high-risk infants (ISRCTN21528841). We built on the European iFAAM consensus guidance to develop a novel food allergy diagnosis algorithm using available information on previous allergenic food ingestion, food reaction(s) and sensitization status. This was implemented by a panel of food allergy experts blind to treatment allocation and OFC outcome. We then evaluated the algorithm's performance in both BEEP and Enquiring About Tolerance (EAT) study participants who did undergo OFC. RESULTS: In 31/69 (45%) BEEP and 44/55 (80%) EAT study control group participants who had an OFC the panel felt confident enough to categorize children as "probable food allergy" or "probable no food allergy". Algorithm-derived panel decisions showed high sensitivity 94% (95%CI 68, 100) BEEP; 90% (95%CI 72, 97) EAT and moderate specificity 67% (95%CI 39, 87) BEEP; 67% (95%CI 39, 87) EAT. Sensitivity and specificity were similar when all BEEP and EAT participants with OFC outcome were included. CONCLUSION: We describe a new algorithm with high sensitivity for IgE-mediated food allergy in clinical study participants who do not undergo OFC. CLINICAL RELEVANCE: This may be a useful tool for excluding food allergy in future clinical studies where OFC is not conducted

How Do Community-based Legal Programs Work: Understanding the Process and Benefits of a Pilot Program to Advance Women's Property Rights in Uganda

This document presents women's property rights, especially access to land, are increasingly recognized as critical to achieving poverty reduction and gender equality. Research shows that community-based legal aid programs are a viable approach to improving legal knowledge and women's access to legal resources to address property issues. From 2009-2010, the International Center for Research on Women (ICRW) and the Uganda Land Alliance (ULA) implemented and evaluated a pilot program to strengthen women's property rights. This report describes the pilot program's implementation, outcomes and lessons. It details the program design, methodologies for monitoring and evaluation, and the context in which the program was implemented. Findings include a discussion of challenges encountered by the rights workers, overall program achievements, and recommendations for community rights work as an approach to promoting women's property rights

Experimental Pulmonary Granuloma Mimicking Sarcoidosis Induced by Propionibacterium acnes in Mice

Propionibacterium acnes has been implicated as an etiologic agent of sarcoidosis since the isolation of this bacterium from sarcoid lesions. We experimentally produced a murine pulmonary granuloma model using P. acnes with several features that simulate sarcoidosis. Mice were sensitized with heat-killed P. acnes and complete Freund's adjuvant and were subsequently challenged with heat-killed P. acnes at 2-week intervals. P. acnes-challenged mice developed epitheloid cell granulomas in the lungs. These mice showed a pulmonary immune response characterized by an increased number of T-lymphocytes, especially CD4 cells, and the ratio of CD4/CD8 in bronchoalveolar lavage (BAL) fluid also increased. Furthermore, significant elevations in both angiotensin-converting enzyme (ACE) serum levels and antibody titers against P. acnes were observed. Mice sensitized with P. acnes without complete Freund's adjuvant were capable of forming pulmonary granulomas, which appeared to be caused by indigenous P. acnes. The genome of P. acnes was found in the lungs, BAL cells, hilar lymph nodes, liver, and spleen in non-sensitized mice, which were thought to be germ-free. These results suggest that the immune response against indigenous P. acnes may play an important role in the pathogenesis of granuloma formation in a murine model.</p