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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Antitumor T-cell Immunity Contributes to Pancreatic Cancer Immune Resistance

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune resistance in pancreatic cancer was induced in response to antitumor T-cell immune responses and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide evidence that T-cell–dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune resistance. Three KPC mouse models of pancreatic cancer were used: the mT3-2D (Kras +/LSL-G12D ; Trp53 +/LSL-R172H ; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-CRE/LSL-Kras/Trp53 flox/flox ) subcutaneous model. KPC cancer cells were grown in immunocompetent and immunodeficient C57BL/6 mice and analyzed to determine the impact of adaptive immunity on malignant epithelial cells, as well as on whole tumors. We found that induced T-cell antitumor immunity, via signal transducer and activator of transcription 1 (STAT1), stimulated malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and altered intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA-approved drug ruxolitinib overcame these tumor-protective responses and improved anti–PD-1 therapeutic efficacy. Overall, these findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection

Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus’s direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2020

A porcine ligated loop model reveals new insight into the host immune response against Campylobacter jejuni

The symptoms of infectious diarrheal disease are mediated by a combination of a pathogen’s virulence factors and the host immune system. Campylobacter jejuni is the leading bacterial cause of diarrhea worldwide due to its near-ubiquitous zoonotic association with poultry. One of the outstanding questions is to what extent the bacteria are responsible for the diarrheal symptoms via intestinal cell necrosis versus immune cell initiated tissue damage. To determine the stepwise process of inflammation that leads to diarrhea, we used a piglet ligated intestinal loop model to study the intestinal response to C. jejuni. Pigs were chosen due to the anatomical similarity between the porcine and the human intestine. We found that the abundance of neutrophil related proteins increased in the intestinal lumen during C. jejuni infection, including proteins related to neutrophil migration (neutrophil elastase and MMP9), actin reorganization (Arp2/3), and antimicrobial proteins (lipocalin-2, myeloperoxidase, S100A8, and S100A9). The appearance of neutrophil proteins also corresponded with increases of the inflammatory cytokines IL-8 and TNF-a. Compared to infection with the C. jejuni wild-type strain, infection with the noninvasive C. jejuni ?ciaD mutant resulted in a blunted inflammatory response, with less inflammatory cytokines and neutrophil markers. These findings indicate that intestinal inflammation is driven by C. jejuni virulence and that neutrophils are the predominant cell type responding to C. jejuni infection. We propose that this model can be used as a platform to study the early immune events during infection with intestinal pathogens.

disease model, INNATE IMMUNITY, proteomics, intest↗
DOE OSTI2018

Active immunization using hand-push emulsification method increases the operator's risk of transcutaneous immunization

Highlights: • Researchers have the right to be told the relevant risks of immunological experiments. • Susceptible individuals to allergic diseases are suggested to be more careful when they perform immunological experiments. Setting up an animal model by using active immunization methods is a common means of studying immune-related diseases or producing antibodies with high titer and high activities. However, the security during the process of pathogen emulsification remains unclear. In a physical examination, we unexpectedly noticed high levels of angiotensin II type 1 receptor autoantibody (AT1-AA) specific to the immunizing antigen in the sera of some researchers who had participated in setting up active immunization animal models, and we were puzzled about the cause of AT1-AA production. In this study, we intended to investigate whether the emulsified antigen was the source of infection in these researchers, and if so, how to prevent it from occurring. AT1-AA was detected by advanced ELISA method. The participants presented higher levels of AT1-AA compared with non-participants of the same laboratory. This phenomenon remained that some factors during the process of rat model establishment may contribute to AT1-AA production. Animal and glove penetration studies indicated the emulsified antigen infection was attributed to neither aerosol or fur touch nor penetrating through gloves. However, AT1-AA level was largely decreased in the participants after they used an automatic emulsification device. Because of the strong permeability of the adjuvant, we speculated that emulsified antigen might get access to the unprotected skin of the participants accidentally during the immunization process. These results demonstrated that accidental contacts of emulsified antigens may infect researchers during the process of traditional hand-push emulsification, resulting in high specific autoantibody levels, which can be prevented by using appropriate tools.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Methods integrating innate and adaptive immune responses in human in vitro immunization assays

Rapid vaccine development and innovative immunotherapeutics are critical in the fight against emerging outbreaks and global pandemic threats, yet the high costs and prolonged timelines for developing new vaccines underscore the urgent need for robust, predictive pre-clinical testing platforms. The rapid down-selection of vaccine candidates and identification of optimal vaccine formulations can be performed using human in vitro immunization (IVI) assays that recapitulate the complex interactions of the innate and adaptive human immune response. In this review, we present a comprehensive evaluation of three key IVI platforms: the whole blood assay (WBA), monocyte-derived dendritic cell (MoDC) assay with dendritic cell-T cell interface assay (DTI), and the microphysiological human tissue construct assay (HTC). The WBA offers a cost-effective and straightforward approach, while the MoDC + DTI system represents the current gold standard for balancing experimental efficiency with immunological complexity. The HTC assay, by mimicking both spatial and temporal aspects of immune interactions, provides enhanced physiological relevance. We discuss the methodological advantages and limitations of each platform, explore their roles in rapid vaccine candidate screening, and propose strategies for integrating these assays with complementary in vivo models. These insights pave the way for refining IVI assays and accelerating the translational pipeline for next-generation vaccines and immunotherapies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Bradbury Science Museum NOTEs Program Docs: Building Immunity: How fighting HIV and other viruses helps us understand our immune system

Building Immunity is a unique opportunity to journey through the history and development of your immune system. Our interactive touch table invites each user to choose their own, unique experience as they learn about how fighting HIV and other viruses helps researchers understand how our own immune systems work to keep us healthy. From the Bradbury Science Museum of Los Alamos National Laboratory, the exhibit presents remarkable insight into one of the most ancient and well-traveled organisms on the planet, viruses. Viral epidemics like the H1N1 flu, which killed over 40 million people in 1918, devastate communities around the world and destabilize regions around the globe. Additionally, their ability to mutate quickly creates a “Red Queen” effect, or loop of treated and then treatment-resistant strains of deadly diseases. Increased understanding of the relationships between viruses and our own immune system is crucial to the development of improved treatments and novel vaccines and this research is happening right now at Los Alamos National Laboratory.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TICAM-1 is dispensable in STING-mediated innate immune responses in myeloid immune cells

Highlights: • A previous paper described that STING signal requires TICAM-1 in mouse MEF. • We have checked TICAM-1 function in STING signal in macrophage/dendritic cells (DCs). • Unlike MEF, mouse macrophages and DCs respond to STING ligands without TICAM-1. • TICAM-1 is dispensable for STING signal in such myeloid cells. Stimulator of interferon genes (STING) is an essential molecule for the production of type I interferon (IFN), and other inflammatory cytokines, in response to cytosolic DNA. STING contributes to host defense against infection and anti-tumor responses. Previous reports have demonstrated that STING signaling is required by the adaptor Toll-IL-1 receptor-containing adaptor molecule-1 (TICAM-1), which has been identified as a TLR3-adaptor molecule using mouse embryonic fibroblasts. Here, we demonstrate that TICAM-1 does not affect STING-mediated innate immune responses, as increases in the mRNA expression levels of IFN-β, IL-6, and CCL5 were observed in bone marrow-derived or splenic myeloid cells. Moreover, STING ligand-enhanced co-stimulatory molecule expression, including CD80, CD86, and CD40, was detected on splenic CD11c + DCs, even in Ticam-1-deficient mice. Our results suggest that STING-mediated innate immune responses and dendritic cell maturation do not require TICAM-1 in myeloid lineage immune cells. TICAM-1 is ubiquitously expressed, even in cell types which do not express TLR3. Therefore, TICAM-1 may possess different functions depending on cell type and signaling purposes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Foreground-Immune Cosmic Microwave Background Lensing with Shear-Only Reconstruction

Cosmic microwave background (CMB) lensing from current and upcoming wide-field CMB experiments such as AdvACT, SPT-3G and Simons Observatory relies heavily on temperature (versus polarization). In this regime, foreground contamination to the temperature map produces significant lensing biases, which cannot be fully controlled by multifrequency component separation, masking, or bias hardening. Here in this Letter, we split the standard CMB lensing quadratic estimator into a new set of optimal “multipole” estimators. On large scales, these multipole estimators reduce to the known magnification and shear estimators, and a new shear B-mode estimator. We leverage the different symmetries of the lensed CMB and extragalactic foregrounds to argue that the shear-only estimator should be approximately immune to extragalactic foregrounds. We build a new method to compute, separately and without noise, the primary, secondary, and trispectrum biases to CMB lensing from foreground simulations. Using this method, we demonstrate that the shear estimator is, indeed, insensitive to extragalactic foregrounds, even when applied to a single-frequency temperature map contaminated with cosmic infrared background, thermal Sunyaev-Zel’dovich, kinematic Sunyaev-Zel’dovich, and radio point sources. This dramatic reduction in foreground biases allows us to include higher temperature multipoles than with the standard quadratic estimator, thus, increasing the total lensing signal-to-noise ratio beyond the quadratic estimator. In addition, magnification-only and shear B-mode estimators provide useful diagnostics for potential residuals.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2020

Arabidopsis calcium-dependent protein kinase 3 regulates actin cytoskeleton organization and immunity

Pattern-triggered immunity and effector-triggered immunity are two primary forms of innate immunity in land plants. The molecular components and connecting nodes of pattern-triggered immunity and effector-triggered immunity are not fully understood. Here, we report that the Arabidopsis calcium-dependent protein kinase CPK3 is a key regulator of both pattern-triggered immunity and effector-triggered immunity. In vitro and in vivo phosphorylation assays, coupled with genetic and cell biology-based analyses, show that actin-depolymerization factor 4 (ADF4) is a physiological substrate of CPK3, and that phosphorylation of ADF4 by CPK3 governs actin cytoskeletal organization associated with pattern-triggered immunity. CPK3 regulates stomatal closure induced by flg22 and is required for resistance to Pst DC3000. Our data further demonstrates that CPK3 is required for resistance to Pst DC3000 carrying the effector AvrPphB. These results suggest that CPK3 is a missing link between cytoskeleton organization, pattern-triggered immunity and effector-triggered immunity.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Evidence that interferon-tau secreted from Day-7 embryo in vivo generates anti-inflammatory immune response in the bovine uterus

Highlights: • Uterine flush (UF) from Day-7 pregnant cows modulates local uterine immunity. • Interferon-tau (IFNT) from Day-7 embryos in the UF mediates this immune modulation. • In vitro stimulation of IFNT induces similar immune regulation in immune cells. • IFNT regulated immune modulation may pave the way for embryo acceptance on Day-7. Recent studies suggest that Day-7 bovine embryo starts to communicate with the uterine epithelium through interferon-tau (IFNT) signaling. However, immune modulatory role of IFNT in the uterus just after the embryo moves from the oviduct is unclear. We aimed to examine the hypothesis that Day-7 bovine embryo secretes IFNT in the uterus, which induces anti-inflammatory response in immune cells. The uterine flush (UF) with multiple embryos was collected from Day-7 donor pregnant cows and peripheral blood mononuclear cells (PBMCs) were then cultured in UF. Transcripts detected in PBMCs revealed that UF from pregnant cows down-regulated pro-inflammatory cytokines (TNFA, IL1B) and up-regulated anti-inflammatory cytokine (IL10) expression, with activation of interferon-stimulated genes (ISGs; ISG15, OAS1) as compared with UF from non-pregnant cows. An addition of specific anti-IFNT antibody to the UF inhibited the effect on PBMCs, indicating that IFNT is a major factor for such immune modulation. The observation that conditioned media from bovine uterine epithelial cells both stimulated with IFNT in vitro and supplemented with fresh IFNT induced similar PBMCs gene expression, confirming that IFNT directly acts on this immune crosstalk. This study shows that IFNT secreted from Day-7 embryo in vivo generates anti-inflammatory response in immune cells, which may provide immunological tolerance to accept the embryo.

60 APPLIED LIFE SCIENCES↗