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Results for “Immune Tolerance”

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 OSTI2025

Insights into regulatory T-cell and type-I interferon roles in determining abacavir-induced hypersensitivity or immune tolerance

Introduction Clinical use of several small molecule drugs may lead to severe T-cell-mediated idiosyncratic drug hypersensitivity reactions (iDHR) linked to HLA alleles, including abacavir (ABC) with HLA-B*57:01. Due to study limitations in humans, pathogenic networks in iDHR remain elusive. HLA transgenic murine models have been proposed to bridge knowledge gaps in tolerance and susceptibility to drugs. Methods Mice expressing HLA-B*57:01 and Foxp3-DTR/EGFP were generated to selectively deplete regulatory T-cells (Treg) with diphtheria toxin. ABC was administered for 8 days alone or together with cell- and cytokine-depleting antibodies. Cellular and transcriptomic responses were analyzed by RNA, flow cytometry and fluorescence methods. Results While CD8 + T-cell responses to ABC require HLA presentation, ABC also triggered mitochondrial stress in macrophagesin vitro, independently of HLA.In vivo, Treg were the primary mechanism of drug tolerance controlling HLA presentation and costimulation by antigen presenting cells. Treg ablation uncovered immune adverse events linked to activation and proliferation of both drug-specific and bystander CD8 + T-cells through CD28-mediated pathways with support from CD4 + non-Treg. Type-I interferon (IFN-I) and cellular-stress pathways influenced the fate of lymph node cells responding to ABC, implicating innate immune cells such as macrophages and plasmacytoid dendritic cells in the development of T-cell responses against the drug. IFN-I and IL-2 were necessary for CD8 + T-cell differentiation and ABC-induced adverse reactions. Conclusions This study unveils novel immune mechanisms driven by drug and host-related factors required forin vivoreactions and sheds light on potential biomarker and therapeutic targets for managing and preventing severe and life-threatening iDHR.

Immunology↗
NASA NTRS2004

Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance.

NASA Discipline Regulatory Physiology↗
DOE OSTI2021

PI3Kαδ Inhibitor Combined With Radiation Enhances the Antitumor Immune Effect of Anti-PD1 in a Syngeneic Murine Triple-Negative Breast Cancer Model

The poor response of breast cancer to immune checkpoint blockade might result from low immunogenicity and the immune-suppressive tumor microenvironment. We hypothesized that in situ tumor vaccination via radiation therapy (RT) and suppression of immune tolerance via phosphoinositide 3-kinase δ (PI3Kδ) inhibition would enhance the efficacy of immune checkpoint blockade.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Structural and physical features that distinguish tumor-controlling from inactive cancer neoepitopes

Neoepitopes arising from amino acid substitutions due to single nucleotide polymorphisms are targets of T cell immune responses to cancer and are of significant interest in the development of cancer vaccines. However, understanding the characteristics of rare protective neoepitopes that truly control tumor growth has been a challenge, due to their scarcity as well as the challenge of verifying true, neoepitope-dependent tumor control in humans. Taking advantage of recent work in mouse models that circumvented these challenges, here, we compared the structural and physical properties of neoepitopes that range from fully protective to immunologically inactive. As neoepitopes are derived from self-peptides that can induce immune tolerance, we studied not only how the various neoepitopes differ from each other but also from their wild-type counterparts. We identified multiple features associated with protection, including features that describe how neoepitopes differ from self as well as features associated with recognition by diverse T cell receptor repertoires. In conclusion, we demonstrate both the promise and limitations of neoepitope structural analysis and predictive modeling and illustrate important aspects that can be incorporated into neoepitope prediction pipelines.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Integrated Metabolomics and Proteomics Analyses in the Local Milieu of Islet Allografts in Rejection versus Tolerance

An understanding of the immune mechanisms that lead to rejection versus tolerance of allogeneic pancreatic islet grafts is of paramount importance, as it facilitates the development of innovative methods to improve the transplant outcome. Here, we used our established intraocular islet transplant model to gain novel insight into changes in the local metabolome and proteome within the islet allograft’s immediate microenvironment in association with immune-mediated rejection or tolerance. We performed integrated metabolomics and proteomics analyses in aqueous humor samples representative of the graft’s microenvironment under each transplant outcome. The results showed that several free amino acids, small primary amines, and soluble proteins related to the Warburg effect were upregulated or downregulated in association with either outcome. In general, the observed shifts in the local metabolite and protein profiles in association with rejection were consistent with established pro-inflammatory metabolic pathways and those observed in association with tolerance were immune regulatory. Taken together, the current findings further support the potential of metabolic reprogramming of immune cells towards immune regulation through targeted pharmacological and dietary interventions against specific metabolic pathways that promote the Warburg effect to prevent the rejection of transplanted islets and promote their immune tolerance.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1997

Antarctic isolation: immune and viral studies

Stressful environmental conditions are a major determinant of immune reactivity. This effect is pronounced in Australian National Antarctic Research Expedition populations exposed to prolonged periods of isolation in the Antarctic. Alterations of T cell function, including depression of cutaneous delayed-type hypersensitivity responses and a peak 48.9% reduction of T cell proliferation to the mitogen phytohaemagglutinin, were documented during a 9-month period of isolation. T cell dysfunction was mediated by changes within the peripheral blood mononuclear cell compartment, including a paradoxical atypical monocytosis associated with altered production of inflammatory cytokines. There was a striking reduction in the production by peripheral blood mononuclear cells of the predominant pro-inflammatory monokine TNF-alpha and changes were also detected in the production of IL-1, IL-2, IL-6, IL-1ra and IL-10. Prolonged Antarctic isolation is also associated with altered latent herpesvirus homeostasis, including increased herpesvirus shedding and expansion of the polyclonal latent Epstein-Barr virus-infected B cell population. These findings have important long-term health implications.

NASA Discipline Environmental Health↗
NASA NTRS1993

Space flight and the immune system

Depression of lymphocyte response to mitogens in cosmonauts after space flight was reported for the first time in the early 1970s by Soviet immunologists. Today we know that depression of lymphocyte function affects at least 50% of space crew members. Investigations on the ground on subjects undergoing physical and psychological stress indicate that stress is a major factor in immune depression of astronauts. This is despite the fact that weightlessness per se has a strong inhibitory effect on lymphocyte activation in vitro. Although the changes observed never harmed the health of astronauts, immunological changes must be seriously investigated and understood in view of long-duration flight on space stations in an Earth orbit, to other planets such as Mars and to the Moon.

NASA Discipline Regulatory Physiology↗
DOE OSTI2021

Current Status of Clinical Trials for Cervical and Uterine Cancer Using Immunotherapy Combined With Radiation

Novel therapies combined with radiation continue to be of significant interest in the developmental treatment paradigm of gynecologic cancers. Clinical implementation of immunotherapy in oncology has rapidly changed the treatment landscape, options, paradigm, and outcomes through clinical trials. Immunotherapy has emerged as a therapeutic pillar in the treatment of solid tumors with demonstrable synergistic activity when combined with radiation therapy and chemoradiotherapy by an alteration or enhancement of the immune system. In solid tumors, radiation therapy induces migration of dendritic cells, T cell activation, and proliferation, and increases in tumor-infiltrating lymphocytes. These immunomodulatory effects in conjunction with immune checkpoint blockade are currently under active investigation in the adjuvant, definitive, and metastatic settings. Results from early phase trials demonstrate promising efficacy and overall tolerable toxicity profiles of combined modality treatment. There is significant interest in optimizing the treatment for patients with locally advanced cervical cancer beyond the standard of care—chemoradiation—which has been in place for the last 30 years. The majority of cervical cancer emerges after persistent infection with a high-risk subtype of the human papillomavirus, where viral oncoproteins lead to cellular changes and immortalization. As a result, immune tolerance can develop, resulting in cancer. Knowledge of the mechanism of human papillomavirus–related oncogenesis suggests that immune therapy or checkpoint blockade can reinvigorate an antitumor immune response. Current clinical trials are exploring the therapeutic potential of these approaches. Uterine cancers have been grouped into 4 molecular subclasses by their driver mutations, mutational burden, and copy-number alterations. Of these subgroups, the polymerase epsilon–mutated and microsatellite-unstable may represent up to 40% of endometrial cancers, and they have been shown to be immunogenic. Because of the inherent immunogenicity of these MSI-high tumors, combined immune modulation strategies, including chemotherapy, radiation, and immunotherapy and immune checkpoint inhibitor therapy, are being explored to improve treatment outcomes. In this review, we explore current immunomodulatory and multimodality therapeutic approaches in the treatment of cervical and uterine cancer through ongoing clinical trials investigating the combination of immunotherapy and radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization

Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clustering a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

IFNgamma-inducible CXCL10/CXCR3 axis alters the sensitivity of HEp-2 cells to ionizing radiation

Highlights: • IFNgamma/CXCL10/CXCR3 are necessary for effective IR-induced HEp-2 cell killing. • Local IR showed fewer effects on tumor burden in mice carrying CXCL10-KO xenografts. • Loss of CXCL10 showed blockage in the G0/G1 phase when exposed to a moderate dose of IR. Radiotherapy is a conventional approach for anti-cancer treatment, killing tumor cells through damaging cellular DNA. While increasing studies have demonstrated that tumors generated the tolerance to radiation and tumor immune system was found to be correlated to radiotherapy resistance. Therefore, it is critical to identify potential immune factors associated with the efficacy of radiotherapy. Here in this study, we evaluated the sensitivities of different tumor cells to radiation and determined HEp-2 cells as the radio-resistant tumor cells for further investigation. IFNgamma as a key regulator of host immune response showed the potential to sensitize tumors to ionizing radiation (IR). Besides, IFNgamma-induced CXC chemokine ligand 10 (CXCL10) was found to be necessary for effective IR-induced killing of cultured HEp-2 cells. Increased clonogenic survival was observed in CXCL10-depleted HEp-2 cells and CXCL10-KO cells. Additionally, the loss of CXCL10 in HEp-2 cells showed less progression of the G0/G1 phase to G2/M when exposed to IR (8 Gy). Local IR (20 Gy) to nude mice bearing HEp-2 tumors significantly reduced tumor burden, while fewer effects on tumor burden in mice carrying CXCL10-KO tumors were observed. We furtherly evaluated the possible roles the chemokine receptor CXCR3 plays in mediating the sensitivity of cultured HEp-2 cells to IR. Altered expression of CXCR3 in HEp-2 cells affected IR-induced killing of HEp-2 cells. Our data suggest the IFNgamma-activated CXCL10/CXCR3 axis may contribute to the effective radiation-induced killing of HEp-2 cells in vitro.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
NASA NTRS2009

Evaluation of a Programmable Voltage-Controlled MEMS Oscillator, Type SiT3701, Over a Wide Temperature Range

Semiconductor chips based on MEMS (Micro-Electro-Mechanical Systems) technology, such as sensors, transducers, and actuators, are becoming widely used in today s electronics due to their high performance, low power consumption, tolerance to shock and vibration, and immunity to electro-static discharge. In addition, the MEMS fabrication process allows for the miniaturization of individual chips as well as the integration of various electronic circuits into one module, such as system-on-a-chip. These measures would simplify overall system design, reduce parts count and interface, improve reliability, and reduce cost; and they would meet requirements of systems destined for use in space exploration missions. In this work, the performance of a recently-developed MEMS voltage-controlled oscillator was evaluated under a wide temperature range. Operation of this new commercial-off-the-shelf (COTS) device was also assessed under thermal cycling to address some operational conditions of the space environment

Patterson, Richard↗
DOE OSTI2021

Evolution of pathogen tolerance and emerging infections: A missing experimental paradigm

Researchers worldwide are repeatedly warning us against future zoonotic diseases resulting from humankind’s insurgence into natural ecosystems. The same zoonotic pathogens that cause severe infections in a human host frequently fail to produce any disease outcome in their natural hosts. What precise features of the immune system enable natural reservoirs to carry these pathogens so efficiently? To understand these effects, we highlight the importance of tracing the evolutionary basis of pathogen tolerance in reservoir hosts, while drawing implications from their diverse physiological and life-history traits, and ecological contexts of host-pathogen interactions. Long-term co-evolution might allow reservoir hosts to modulate immunity and evolve tolerance to zoonotic pathogens, increasing their circulation and infectious period. Such processes can also create a genetically diverse pathogen pool by allowing more mutations and genetic exchanges between circulating strains, thereby harboring rare alive-on-arrival variants with extended infectivity to new hosts (i.e., spillover). Finally, we end by underscoring the indispensability of a large multidisciplinary empirical framework to explore the proposed link between evolved tolerance, pathogen prevalence, and spillover in the wild.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2008

Performance of MEMS Silicon Oscillator, ASFLM1, under Wide Operating Temperature Range

Over the last few years, MEMS (Micro-Electro-Mechanical Systems) resonator-based oscillators began to be offered as commercial-off-the-shelf (COTS) parts by a few companies [1-2]. These quartz-free, miniature silicon devices could compete with the traditional crystal oscillators in providing the timing (clock function) for many digital and analog electronic circuits. They provide stable output frequency, offer great tolerance to shock and vibration, and are immune to electro-static discharge [1-2]. In addition, they are encapsulated in compact lead-free packages, cover a wide frequency range (1 MHz to 125 MHz), and are specified, depending on the grade, for extended temperature operation from -40 C to +85 C. The small size of the MEMS oscillators along with their reliability and thermal stability make them candidates for use in space exploration missions. Limited data, however, exist on the performance and reliability of these devices under operation in applications where extreme temperatures or thermal cycling swings, which are typical of space missions, are encountered. This report presents the results of the work obtained on the evaluation of an ABRACON Corporation MEMS silicon oscillator chip, type ASFLM1, under extreme temperatures.

Patterson, Richard L.↗
NASA NTRS2009

Assessment of Operation of EMK21 MEMS Silicon Oscillator Over Wide Temperature Range

Electronic control systems, data-acquisition instrumentation, and microprocessors require accurate timing signals for proper operation. Traditionally, ceramic resonators and crystal oscillators provided this clock function for the majority of these systems. Over the last few years, MEMS (Micro-Electro-Mechanical Systems) resonator-based oscillators began to surface as commercial-off-the-shelf (COTS) parts by a few companies. These quartz-free, miniature silicon devices could easily replace the traditional crystal oscillators in providing the timing/clock function for many digital and analog circuits. They are reported to provide stable output frequency, offer great tolerance to shock and vibration, and are immune to electro-static discharge [ 1-2]. In addition, they are encapsulated in compact lead-free packages and cover a wide frequency range (1 MHz to 125 MHz). The small size of the MEMS oscillators along with their thermal stability make them ideal candidates for use in space exploration missions. Limited data, however, exist on the performance and reliability of these devices under operation in applications where extreme temperatures or thermal cycling swings, which are typical of space missions, are encountered. This report presents the results of the work obtained on the evaluation of an Ecliptek Corporation MEMS silicon oscillator chip under extreme temperatures.

Patterson, Richard L.↗
NASA NTRS1990

Networks for image acquisition, processing and display

The human visual system comprises layers of networks which sample, process, and code images. Understanding these networks is a valuable means of understanding human vision and of designing autonomous vision systems based on network processing. Ames Research Center has an ongoing program to develop computational models of such networks. The models predict human performance in detection of targets and in discrimination of displayed information. In addition, the models are artificial vision systems sharing properties with biological vision that has been tuned by evolution for high performance. Properties include variable density sampling, noise immunity, multi-resolution coding, and fault-tolerance. The research stresses analysis of noise in visual networks, including sampling, photon, and processing unit noises. Specific accomplishments include: models of sampling array growth with variable density and irregularity comparable to that of the retinal cone mosaic; noise models of networks with signal-dependent and independent noise; models of network connection development for preserving spatial registration and interpolation; multi-resolution encoding models based on hexagonal arrays (HOP transform); and mathematical procedures for simplifying analysis of large networks.

Ahumada, Albert J., Jr.↗