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At least 109 records · Page 6

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DOE OSTI2025

scRNA seq of an F1 cross of Marek’s disease resistant and susceptible chickens identifies allele specific expression signatures enriched in transcription modulators

Abstract Marek’s disease (MD), a T cell lymphoma disease in chickens, is caused by the Marek’s disease virus (MDV) found ubiquitously in the poultry industry. Genetically resistant Line 6 3 (L6) and susceptible Line 7 2 (L7) chickens have been instrumental to research on avian immune system response to MDV infection. In this study we characterized molecular signatures unique to splenic immune cell types across different genetic backgrounds 6 days after infection. Using three populations, L6, L7, and an F1 cross between L6xL7, we evaluated the immune cell transcriptome of responding cell types using single cell RNA sequencing. Several MDV genes were found expressed mainly in cytotoxic T cells while ICP4 and MEQ MDV genes were expressed across infected cell types. Using the F1 we quantified allele specific expression (ASE) of biallelic SNPs and found biased expression of parental alleles specific to immune cell subtypes. We identified 22 SNPs with ASE in response to MDV infection mapped to gene rich regions surrounding 59 genes of critical importance for chromatin remodeling and transcriptional regulation. Histone deacetylase genes (HDAC1 and HDAC8) had increased expression of L6 alleles, while small nuclear RNA genes (SNORA68 and SNORA72) expressed higher levels of L7 alleles with infection in T cell subsets. SNPs with ASE also mapped genes important for an adequate immune response including GNLY (cytotoxic activity) and PDIA3 (component of MHC class I peptide loading complex), and genes known to promote viral replication (MCM5 and EIF3M). These results show that functional variants associated with susceptibility to MD may have a bigger impact in subsets of immune cell types, and by characterizing the transcriptomes of these subtypes we can unravel molecular signatures specific to MD genomic resistance.

Science & Technology - Other Topics↗

DOE OSTI2020

Metabolite releasing polymers control dendritic cell function by modulating their energy metabolism

Metabolites control immune cell functions, and delivery of these metabolites in a sustained manner may be able to modulate function of the immune cells. In this study, alpha-ketoglutarate (aKG) and diol based polymeric-microparticles (termed paKG MPs) were synthesized to provide sustained release of aKG and promote an immunosuppressive cellular phenotype. Notably, after association with dendritic cells (DCs), paKG MPs modulated the intracellular metabolic-profile/pathways, and decreased glycolysis and mitochondrial respiration in vitro. These metabolic changes resulted in modulation of MHC-II, CD86 expression in DCs, and altered the frequency of regulatory T cells (Tregs), and T-helper type-1/2/17 cells in vitro. In conclusion, this unique strategy of intracellular delivery of key-metabolites in a sustained manner provides a new direction in immunometabolism field-based immunotherapy with potential applications in different diseases associated with immune disorders.

36 MATERIALS SCIENCE↗

DOE OSTI2022

Metal Hydride Compressor for High-Pressure (875 bar) Hydrogen Delivery

Metal hydride hydrogen compression utilizes a reversible heat-driven interaction of a hydride-forming metal alloy with hydrogen gas. This paper reports on the development of a laboratory scale two-stage Metal Hydride Compressor (MHC) system with a feed pressure of 150 bar delivering high purity H2 gas at outlet pressures up to 875 bar. Stage 1 and stage 2 AB 2 metal hydrides are identified based on experimental characterization of the pressure-composition-temperature (PCT) behavior of candidate materials. The selected metal hydrides are each combined with expanded natural graphite, increasing the thermal conductivity of the composites by an order of magnitude. These composites are integrated in two compressor beds with internal heat exchangers that alternate between hydrogenation and dehydrogenation cycles by thermally cycling between 20 °C and 150 °C. The prototype compressor achieved compression of hydrogen from 150 bar to 700 bar with an average flow rate of 33.6 g/hr.

08 HYDROGEN↗

DOE OSTI2024

Evaluation of the Radioactive Material Release in the Harborview Research and Training Building and Implications for Emergency Response

On May 2, 2019, during the 137 Cs source recovery operation, a source capsule in a research irradiator containing approximately 77.1 TBq was breached. Based on a geometric reconstruction analysis of the damage to the capsule, approximately 46.3 GBq (0.04%) was impacted by the chop saw (grinder) inside a Mobile Hot Cell (MHC) on the loading dock at the University of Washington Harborview Research and Training (HRT) Building. A very small fraction of the material impacted, less than 1%) was released from the Mobile Hot Cell and then to the rest of the HRT Building. The objectives of this project were to assess the accidental release of 137 CsCl and its implications related to emergency response methods and the ramifications of 137 CsCl transport. The phenomenology of this event was also compared with past alkali halide dispersal events. The vast number of measurements and samples collected by the remediation contractors, the Department of Energy's Nuclear Emergency Support Team, and the small number of retrospective samples collected by the authors informed the analysis. The techniques included (1) autoradiography and electron microscopy of samples collected from the HRT Building and the irradiator, (2) 3D visualization of deposition on surfaces and within the ventilation system, and (3) a study of the damage to the source capsule to evaluate the Cs particle size and particle composition due to the grinding accident. Subsequently, the cesium contaminant transport through the numerous pathways in the building was reconstructed to assess the deposition on surfaces as a function of particle size. The implications for emergency response are relevant to data quality and management. A Data Quality Objective (DQO) guides data collection methods so that they have appropriate accuracy and precision for the intended application. Recommendations were made with respect to the sample collection protocols and sample archival.

61 RADIATION PROTECTION AND DOSIMETRY↗

NASA NTRS1992

Rat soleus muscle fiber responses to 14 days of spaceflight and hindlimb suspension

Morphological and enzymatic responses in fibers of different types were studied in rats after 14 days of spaceflight onboard Cosmos 2044 or hindlimb suspension. Fibers were classified as fast-twitch, slow-twitch, or both fast- and slow-twitch on the basis of the type of myosin heavy chains (MHC). Data obtained indicate that during the 14 days of spaceflight or suspension the protein profiles of 9-14 percents of the slow-twitch fibers reconfigured from typical slow-twitch toward fast switch fibers, while all fibers were dramatically losing total protein. These results were consistent with the data obtained from Cosmos 1887 and Skylab 3. It is suggested that effects of spaceflight on skeletal muscle can be attributed to a dramatic reduction in the level and/or pattern of loading.

Ohira, Yoshi↗

NASA NTRS1992

Adaptation of fibers in fast-twitch muscles of rats to spaceflight and hindlimb suspension

The adaptation of single fibers in medial gastrocnemius (MG), a fast-twitch extensor, and in tibialis anterior (TA), a fast-twitch flexor, was studied after 14 days of spaceflight onboard Cosmos 2044 or hindlimb suspension. Quantitative myosin ATPase activities of single fibers were measured in flight and suspended rats. Each of the enzyme and size measurements were directly correlated within each fiber with respect to its qualitative myosin ATPase staining properties and its expression of fast, slow, or both myosin heavy chains (MHC). The percentage of slow- and fast-twitch fibers of the MG and TA were found to be unchanged. Mean fiber size of all fibers was unaffected after flight or suspension. The ATPase activity in the MG was higher in flight than in control or suspended rats. In comparison to Cosmos 1887 spaceflight, the adaptations in the muscle fibers of the MG were more moderate.

Jiang, Bian↗

NASA NTRS1997

Studies of Cell-Mediated Immunity Against Immune Disorders Using Synthetic Peptides and Rotating Bioreactor System

Our proposed experiments included: (1) immunzing mice with synthetic peptides; (2) preparing spleen and lymph node cells; (3) growing them under conventional conditions as well as in the rotatory vessel in appropriate medium reconstituting with synthetic peptides and/or cytokines as needed; and (4) comparing at regular time intervals the specific CTL activity as well as helper T-cell activity (in terms of both proliferative responses and cytokine production) using established procedures in my laboratory. We further proposed that once we demonstrated the merit of rotatory vessel technology to achieve desired results, these studies would be expanded to include immune cells from non-human primates (rhesus monkeys and chimpanzees) and also humans. We conducted a number of experiments to determine CTL induction by the synthetic peptides corresponding to antigenic proteins in HIV and HPV in different mouse strains that express MHC haplotypes H-2b or H-2d. We immunized mice with 100 ug of the synthetic peptide, suspended in sterile water, and emulsified in CFA (1:1). The immune lymph node cells obtained after 7 days were restimulated by culturing in T25 flask, HARV-10, or STLV-50, in the presence of the peptide at 20 ug/ml. The results from the 5'Cr-release assay consistently revealed complete abrogation of CTL activity of cells grown in the bioreactors (both HARV and STLV), while significant antigen-specific CTL activity was observed with cells cultured in tissue culture flasks. Thus, overall the data we generated in this study proved the usefulness of the NASA-developed developed technology for understanding the known immune deficiency during space travel. Additionally, this ex vivo microgravity technology since it mimics effectively the in vivo situation, it is also useful in understanding immune disorders in general. Thus, our proposed studies in TMC-NASA contract round II application benefit from data generated in this TMC-NASA contract round I study.

Sastry, Jagannadha K.↗

NASA NTRS1998

Studies of Cell-Mediated Immunity Against Immune Disorders Using Synthetic Peptides and Rotating Bioreactor System

We conducted a series of experiments using mouse immune-precursor cells, and observed that bioreactor culturing results in the loss of antigen-specific cytotoxic T lymphocyte (CTL) function. The reason for the abrogation of CTL function is microgravity conditions in the bioreactor, but not the antigen per se or its MHC restriction. Similarly, we observed that allostimulation of human PBMC in the bioreactor, but not in the T flask, resulted in the blunting of both allo-CTL function and the NK activity, indicating that the microgravity-associated functional defects are not unique to the mouse system. These results provide further confirmation to the microgravity-associated immune dysfunction, and constitute ground-based confirmatory data for those related to space-travel.

Sastry, Jagannadha K.↗

NASA NTRS2003

Basic and clinical immunology

Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.

Review↗

NASA NTRS2000

Fiber size and myosin phenotypes of selected rhesus lower limb muscles after a 14-day spaceflight

Muscle biopsies were taken from the rhesus (Macaca mulatta) soleus (Sol, a slow ankle extensor), medial gastrocnemius (MG, a fast ankle extensor), tibialis anterior (TA, a fast ankle flexor), and vastus lateralis (VL, a fast knee extensor) muscles in vivarium controls (n=5) before and after either a 14-day spaceflight (Bion 11, n=2) or a 14-day ground-based flight simulation (n=3). Myosin heavy chain (MHC) composition (gel electrophoresis), fiber type distribution (immunohistochemistry), and fiber size were determined. Although there were no significant changes, each muscle showed trends towards adaptation.

NASA Discipline Musculoskeletal↗

NASA NTRS1994

The effects of space flight on the contractile apparatus of antigravity muscles: implications for aging and deconditioning

Previous studies have shown that the unloading of skeletal muscle, as occurring during exposure to space flight, exerts a profound effect on both the mass (cross sectional area) of skeletal muscle fibers and the relative expression of protein isoforms comprising the contractile system. Available information suggests that slow (type I) fibers, comprising chiefly the antigravity muscles of experimental animals, in addition to atrophying, undergo alterations in the type of myosin heavy chain (MHC) expressed such that faster isoforms become concomitantly expressed in a sub-population of slow fibers when insufficient force-bearing activity is maintained on the muscle. Consequently, these transformations in both mass and myosin heavy chain phenotype could exert a significant impact on the functional properties of skeletal muscle as manifest in the strength, contractile speed, and endurance scope of the muscle. To further explore these issues, a study was performed in which young adult male rats were exposed to zero gravity for six days, following which, the antigravity soleus muscle was examined for a) contractile properties, determined in situ and b) isomyosin expression, as studied using biochemical, molecular biology, and histochemical/immunohistochemical techniques.

Flight Experiment↗

NASA NTRS1994

Class I and class II major histocompatibility molecules play a role in bone marrow-derived macrophage development

Class I and class II major histocompatibility complex (MHC) molecules play significant roles in T cell development and immune function. We show that MHCI- and MHCII-deficient mice have low numbers of macrophage precursors and circulating monocytes, as well as abnormal bone marrow cell colony-stimulating factor type 1 secretion and bone composition. We suggest that MHCI and MHCII molecules play a significant role in macrophage development.

Non-NASA Center↗

NASA NTRS2005

Alterations in Vasoreactivity of Femoral Artery Induced by Hindlimb Unweighting are Related to the Changes of Contractile Protein in Rats

Responses of endothelium removed femoral arterial rings to vasoactive compounds were examined in vitro, and the expression of Myosin and Actin of femoral artery were observed by Western Blotting and Immunohistochemistry in hndlimb unweighting rats and control rats. The results showed that contractile responses of femoral arterial rings evoked by Phenylephrine, Endothelin-1, Vasopressin, KCl, Ca(2+) and Ca(2+) ionophore A23187 were decreased in hindlimb unweighting rats as compared with that of controls. But vasoddatory responses induced by SNPand cGMP were not different between groups. No significant differences have been found in expressions of Calponin, Myosin, Actin, and the ratio of MHC SM1/SM2 between the two groups, but expression of alpha-SM-Actin decreased in hindlimb unweighting rats. The data indicated that the diminished contractile responsiveness probably result from altered contractile apparatus, especially the contractile proteins.

Ma, Jin↗

NASA NTRS2010

Immune System Dysregulation and Herpesvirus Reactivation Persist During Long-Duration Spaceflight

Background: Immunity, latent herpesvirus reactivation, physiological stress and circadian rhythms were assessed during six month spaceflight onboard ISS. Blood and saliva samples were collected early, mid and late in-flight and returned for immediate analysis. Mid-point study data (10 of 17 planned subjects) will be presented. Results: Some shifts in leukocyte distribution occurred during flight, including alterations in CD8+ T cell maturation. General T cell function was consistently reduced early in-flight. Levels CD8+/IFNg+ producing T cells were depressed early in-flight, and immediately upon landing. Persistent mitogen-dependant reductions were observed in IFNg, IL-17a, IL-10, TNFa and IL-6 production. Monocyte production of IL-10 was reduced, whereas IL-8 levels were increased. Levels of mRNA for the TNFa, IL-6 and IFNg were transiently elevated early in-flight, and the dynamics of TNF and IL-6 gene expression were somewhat antagonistic to their corresponding receptors during flight. The number of virus-specific CD8+ T-cells was measured using MHC tetramers, while their function was measured using intracellular cytokine analysis following peptide stimulation. Both the number and function of EBV-specific cells decreased during flight as compared to preflight levels. The number of CMV-specific T-cells generally increased as the mission progressed while their function was variable. Viral (EBV) load in blood was elevated postflight. Anti-EBV VCA antibodies were significantly elevated by R+0; anti-EA antibodies were not significantly elevated at landing; and anti-CMV antibodies were somewhat elevated during flight. Higher levels of salivary EBV DNA were found during flight. VZV DNA reactivation occurred in ~50 % of astronauts during flight, continuing for up to 30 days post-flight. CMV was shed in 35 % the in-flight and 30% of postflight urine samples of the crewmembers. There was generally a higher level of cortisol as measured in urine and saliva in the astronauts during flight, but plasma cortisol was relatively unchanged during flight. Circadian rhythm of salivary cortisol was altered during flight. Conclusion. Some alterations in immunity do not resolve during six month spaceflight, consequentially resulting in persistent herpesvirus reactivation. Ongoing immune dysregulation may represent specific clinical risks for exploration-class space missions.

Crucian, B. E.↗

NASA NTRS2011

Altered Innate and Lymphocytic Immune Responses in Mouse Splenocytes Post-Flight

Space flight is known to affect immune responses of astronauts and animals, decreasing lymphocytic responses to mitogenic stimuli, delayed typed hypersensitivity reactions, and T-cell activation. Despite changes in immune suppression, there are no reports of consistent adverse clinical events post flight. To further investigate the spectrum of affected immune responses, murine splenocytes were stimulated immediately post-shuttle flight (14 days on STS-135) with T-cell stimulators or toll-like receptor agonists. Comparisons were made to ground control splenocytes from age-matched mice. Cell phenotypes were assessed, as well as activation markers and associated cytokine production. The CD4+ population decreased with no concurrent decrease in CD8+ cells from shuttle mice post flight compared to ground controls. Regarding antigen presenting cell populations, the number of CD11c+ cells were slightly elevated post flight, compared to ground controls, with increased MHC Class I expression (I-A(sup b)) and no change in Class II expression (H-2K(sup b)). CD86+ populations were also significantly diminished. However, the decreased markers did not correlate with activity. Stimulation of splenocytes post flight showed significant increase in bead uptake, increased Class I expression, increased TNF-alpha and IL-6 production in response to TLR-2 (zymosan) and TLR-4 (LPS) agonists. While most activated (ConA or anti-CD3/anti-CD28) CD4+ cells showed markedly diminished responses (reduced IL-2 production), non-specific T cell responses to superantigen (SEA/SEB) increased post flight as determined by expression of early activation markers. Production of additional cytokines was also dysregulated postflight. Overall, persistent immune changes during space flight could represent unique clinical risks for exploration class missions. The consequences of pathogenic encounter remain an important concern that should be addressed.

Hwang, ShenAn↗

DOE OSTI2023

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses

Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs

The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Targeting of intracellular oncoproteins with peptide-centric CARs

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

60 APPLIED LIFE SCIENCES↗