Tolerance To Conditions Research Articles

Recovery from virus infection: plant’s armory in action

This review focuses on different factors involved in promoting symptom recovery in plants post-virus infection such as epigenetics, transcriptional reprogramming, phytohormones with an emphasis on RNA silencing as well as role of abiotic factors such as temperature on symptom recovery. Plants utilize several different strategies to defend themselves in the battle against invading viruses. Most of the viral proteins interact with plant proteins and interfere with molecular dynamics in a cell which eventually results in symptom development. This initial symptom development is countered by the plant utilizing various factors including the plant's adaptive immunity to develop a virus tolerant state. Infected plants can specifically target and impede the transcription of viral genes as well as degrade the viral transcripts to restrict their proliferation by the production of small-interfering RNA (siRNA) generated from the viral nucleic acid, known as virus-derived siRNA (vsiRNA). To further escalate the degradation of viral nucleic acid, secondary siRNAs are generated. The production of virus-activated siRNA (vasiRNA) from the host genome causes differential regulation of the host transcriptome which plays a major role in establishing a virus tolerant state within the infected plant. The systemic action of vsiRNAs, vasiRNA, and secondary siRNAs with the help of defense hormones like salicylic acid can curb viral proliferation, and thus the newly emerged leaves develop fewer symptoms, maintaining a state of tolerance.

A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke

Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR)–hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.Graphical

Abstract 1668: Targeting drug-induced tolerant & resistant cell populations by novel ferroptosis inducer

Abstract A subset of tumor cells escapes apoptotic and necroptotic death when subjected to chemo- or targeted therapy thereby entering a transient reversible less-proliferative “tolerant state.” Upon continuous drug treatment, these tumor cells become drug resistant, leading to metastases and cancer relapse. A long-standing goal in oncology has been to develop therapeutics to effectively target both cell states. Growing published evidence suggests that accumulation of reactive oxygen species and lipid remodeling make tolerant and resistant tumor cells more vulnerable to ferroptotic mode of cell death. To this end, we here characterize the activity of a proprietary inhibitor of GPX4, an enzyme that safeguards against ferroptosis, across a panel of tolerant and resistant cell line models. Drug tolerant and resistant cancer cell lines spanning three indications were generated by applying continuous treatments with relevant standard-of-cares (SOC) in vitro for short or long durations, respectively. Age-matched control cell lines were derived in parallel by treatment of parental cells with DMSO. Cells were subjected to high dose of SOC for nine days to generate tolerant lines, or to increased therapeutic doses of SOC over three months to generate resistant lines, after which resistance to SOCs was confirmed. In accordance with our hypothesis, we found that drug tolerant lines demonstrated enhanced sensitivity to GPX4 inhibition compared to age-matched control lines. Furthermore, we noted that resistant tumor cell lines retained exquisite sensitivity to GPX4 inhibition across all indications while demonstrating up to 1000-fold resistance to SOCs. In summary, we found that cell line models which evade cell death upon treatment with chemo- or targeted therapies continued to present vulnerability to ferroptosis induction across both cell states. Given the heterogeneity in responses to drug-induced cell-states, understanding the mechanisms of differential drug sensitivity to GPX4 inhibition may help in formulating successful strategies for targeting this relevant cell population in the clinic, thereby limiting cancer progression and/or improving curative potential. Citation Format: Taronish Dubash, Maria Cristina Munteanu, Shrouq Farah, Cristian Nunez, Laurence Jadin, Branko Radetich, Darby Schmidt, Nadia Gurvich. Targeting drug-induced tolerant & resistant cell populations by novel ferroptosis inducer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1668.

Immunological reactivity in calves obtained from revaccinated cows during immunization with vaccines from B.abortus strains 19, 104M and 82

The system of anti-brucellosis measures requires constant improvement in order to increase its effectiveness and reliability. At the same time, the priority remains the creation of high specific protection for brucellosis in animals. Live vaccines from agglutinogenic strains of B.abortus 19, 104M and 82 turned out to be the most immunogenic and effective in antiepizootic relation. As a result of the conducted studies, it was found that the most pronounced general and local reactions were noted in calves vaccinated subcutaneously with a standard dose of vaccine from strain 19, less pronounced in vaccinated with vaccine from strain 104M and weakly in vaccinated with vaccine from strain 82. According to the results of serological studies of blood serum, it can be seen that all animals (100%) reacted in calves for 10-20 days after immunization with vaccines from strains 19 and 104M, and only 40% of calves vaccinated with vaccine from strain 82 reacted. At the same time, calves vaccinated with the strain 19 vaccine reacted in RA in the titers 400-1600 ME. Vaccine from strain 104M - in titers 400-800 ME, vaccine from strain 82 - in titers 25-50 ME. According to the results of serological studies, the state of tolerance was not noted in calves received from re-immunized cows after immunization with agglutinogenic anti-brucellosis vaccines. Further study of the dynamics of antibodies after the introduction of vaccines from strains 19, 104М and 82 by subcutaneous method in a full dose to calves of 3-5 months of age received from re-vaccinated cows showed that the timing of the maximum rise and extinction of the titers of agglutinating and complement-binding antibodies in the blood serum of vaccinated animals is also directly dependent on the properties of the vaccine used. Thus, as a result of serological studies, it was found that the repeated reimunization of pregnant cows with vaccines from strains B.abortus 19, 104M and 82 have no significant effect on the immunological reactivity of the offspring obtained from them, which is confirmed by the absence of a state of tolerance in calves after immunization with agglutinogenic anti-brucellosis vaccines.

Paediatric Obesity Evaluation for Metabolic Susceptibility (POEMS)

IntroductionOur aim was to determine whether there are risk factors which increase the risk of developing dysglycemia in a child who has increased body mass index (BMI) (overweight/obese).Research design and...

Staphylococcus aureus induces tolerance in human monocytes accompanied with expression changes of cell surface markers.

Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1β) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus-stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed.

A Lesson of Immunosuppression in Renal Transplant: Retreat or Hold?

Background: Aiming at understanding whether there are cases of near-tolerance among long-term surviving kidney transplant recipients in our center, or even operant tolerance can be attempted based on their immune status, we analyzed changes of immune cell subsets and cytokines in various groups, and evaluated immune status of long-term survival recipients. Methods: A real-world, observational, retrospective cohort study was conducted in our hospital. Twenty-eight long-term recipients were selected as study subjects, 15 recent postoperative stable recipients, and 15 healthy subjects as controls. T and B lymphocyte subsets, MDSCs, and cytokines were detected and analyzed. Results: Treg/CD4 T cells, total B and B10 cells in long-term and recent renal recipients were lower than healthy controls (HC). The level of IFN-γ and IL-17A in long-term survival patients was obviously higher than that in recent postoperative stable recipients and HC, while TGF-β1 level was significantly lower in long-term survival group than in short-term postoperative group and HC. Notably, compared with short-term recipients, it has been found that the IL-6 level in both positive and negative HLA groups were obviously lower (all P<0.05). In the long-term survival group, 43% of recipients were positive for urinary protein and 50% were positive for HLA antibody. Conclusion: This "real-world" study validates the findings of real status of long-term survival recipients observed in clinical trials. Contrary to a state of proper tolerance as expected, the group recipients in long-term survival were accompanied by the increased indicators of immune response, while those related to immune tolerance were not significantly increased. Long-term survival recipients with stable renal function may be in an immune equilibrium state where immunosuppression and rejection coexist under the action of low-intensity immune agents. If immunosuppressive agents are reduced or even removed, rejection may occur.

Особливості функціонування імунологічної толерантності під час вагітності (огляд літератури)

Pregnancy is a special state in a woman’s life, which can definitely be considered an «immunological paradox», because the growth of a genetically «alien» fetus takes place in a woman’s body. Despite the direct contact between cells of fetal origin (syncytiotrophoblast) and cells of the maternal immune system, which are in excess in the decidual membrane of the uterus, rejection of the semi-allogeneic fetus does not occur. A state of permanent natural immunological tolerance, during which the body does not respond to certain antigens expressed by trophoblast cells, while maintaining the ability to respond immunologically to other immunogens is the opposite phenomenon of the immune response, it is acquired by the body during its development and is not genetically determined. Purpose - to analyze the phasing of immunological changes in the mother’s body, which are aimed at the development and preservation of pregnancy, to specify their role in the correct flow of placental waves, prevention of the development of placental dysfunction and obstetric complications associated with it. A review of modern medical literature on the processes of immunological changes during trophoblast invasion and placentation in early pregnancy is given. For a more detailed understanding, the influence of each link of the immune response in the process of developing immune tolerance was analyzed. It has been established that for the development of a normal pregnancy there is a genetically programmed immune mechanism that ensures a decrease in the local and systemic immune response to the semi-alien implanted blastocyst, embryo and fetus. This is achieved through the step-by-step course of three phases of immunological shifts: the unfolded immune conflict; suppression of the immune response and intense immune conflict. The physiological course of gestation and the development of the placenta, in which the balance between the processes of neoangiogenesis and apoptosis is maintained, is ensured by adequate expression of HLA-G locus molecules by trophoblast cells, inhibition of Th1-type cytotoxic reactions against placenta cells by the mother's body. Analyzed changes in the cytokine balance, which shifts towards immunosuppressive cytokines, which suppress cellular immune reactions and stimulate the production of blocking antibodies, the quantitative composition of which can be considered decisive when carrying a genetically foreign fetus. Consequently, a relative secondary cellular immunodeficiency is formed, which is mainly due to a deficiency of circulating T-helper/inducers, a decrease in the CD4/CD8 immunoregulatory index and suppression of the functional activity of the T-cell immune system. It has been proven that impaired immunological tolerance, trophoblast invasion and vascular remodelling processes controlled by the maternal immune system at the local and systemic levels lead to early reproductive losses, premature birth, placental dysfunction, and are associated with fetal growth retardation syndrome, pre-eclampsia and other complications. No conflict of interests was declared by the authors.

Identification of a Small Molecule Compound Active against Antibiotic-Tolerant Staphylococcus aureus by Boosting ATP Synthesis

Antibiotic tolerance poses a threat to current antimicrobial armamentarium. Bacteria at a tolerant state survive in the presence of antibiotic treatment and account for persistence, relapse and recalcitrance of infections. Antibiotic treatment failure may occur due to antibiotic tolerance. Persistent infections are difficult to treat and are often associated with poor prognosis, imposing an enormous burden on the healthcare system. Effective strategies targeting antibiotic-tolerant bacteria are therefore highly warranted. In this study, small molecule compound SA-558 was identified to be effective against Staphylococcus aureus that are tolerant to being killed by conventional antibiotics. SA-558 mediated electroneutral transport across the membrane and led to increased ATP and ROS generation, resulting in a reduction of the population of antibiotic-tolerant bacteria. In a murine chronic infection model, of which vancomycin treatment failed, we demonstrated that SA-558 alone and in combination with vancomycin caused significant reduction of MRSA abundance. Our results indicate that SA-558 monotherapy or combinatorial therapy with vancomycin is an option for managing persistent S. aureus bacteremia infection and corroborate that bacterial metabolism is an important target for counteracting antibiotic tolerance.

Deterministic or probabilistic? - A survey on Byzantine fault tolerant state machine replication

Byzantine Fault tolerant (BFT) protocols are implemented to guarantee the correct system/application behavior even in the presence of arbitrary faults (i.e., Byzantine faults). Byzantine Fault tolerant State Machine Replication (BFT-SMR) is a known software solution for masking arbitrary faults and malicious attacks (Liu et al., 2020). In this survey, we present and discuss relevant BFT-SMR protocols, focusing on deterministic and probabilistic approaches. The main purpose of this paper is to discuss the characteristics of proposed works for each approach, as well as identify the trade-offs for each different approach.

Training vs. Tolerance: The Yin/Yang of the Innate Immune System.

For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has been challenged by an increasing number of studies revealing that innate immune cells are capable of exhibiting memory-like features resulting in increased responsiveness to subsequent challenges, a process known as trained immunity (known also as innate memory). In contrast, the refractory state of endotoxin tolerance has been defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both training as well tolerance as adaptive features are reported to be accompanied by epigenetic and metabolic alterations occurring in cells. While training conveys proper protection against secondary infections, the induction of endotoxin tolerance promotes repairing mechanisms in the cells. Consequently, the inappropriate induction of these adaptive cues may trigger maladaptive effects, promoting an increased susceptibility to secondary infections-tolerance, or contribute to the progression of the inflammatory disorder-trained immunity. This review aims at the discussion of these opposing manners of innate immune and non-immune cells, describing the molecular, metabolic and epigenetic mechanisms involved and interpreting the clinical implications in various inflammatory pathologies.

BRUCELLA ECOLOGY AND DIAGNOSTICS OF BRUCELLOSIS (REVIEW)

Review of domestic and foreign scientific literature on brucella ecology, brucellosis epizootology and pathogenesis is presented. It has been found that the main route of transmitting the infection causative agents is vertical. At the same time the newborns receive such a small dose of brucella that for a long time it is impossible to confirm them being infected by the conventional diagnostic methods. The deterioration of the epizootic situation is explained precisely by the following – young cattle bred from sick cows are integrated in the broodstock. In this case many of them remain hidden carriers of the pathogen and do not respond to diagnostic tests (a state of tolerance). Young cattle infected with brucella are detected only after they become an active source of infection causing epizootic danger during 2–4 years, i.e. before calving or abortion, still remaining the undetected source of the pathogen. At the same time the conventional diagnostic methods are practically ineffective. In this case the diagnostic method based on the immunological tolerance phenomenon implying the use of the vaccine from the strain B. abortus 19 is applied, this is a serological test to detect the negatively responsive to brucellosis heifers that are 15–20 days after vaccination and to bar them from herd reproduction. In addition, when diagnosing brucellosis, it is necessary to take into account the latent course of the disease in adult animals. It is possible to reveal hidden carriers of brucella by provoking latent infection through immunisation with vaccines from the R-strains B. abortus 1096 or RV-51, which ensures the pathogen devastation.

The Effect and Mechanism of Corilagin from Euryale Ferox Salisb Shell on LPS-Induced Inflammation in Raw264.7 Cells.

(1) Background: Euryale ferox Salisb is a large aquatic plant of the water lily family and an edible economic crop with medicinal value. The annual output of Euryale ferox Salisb shell in China is higher than 1000 tons, often as waste or used as fuel, resulting in waste of resources and environmental pollution. We isolated and identified the corilagin monomer from Euryale ferox Salisb shell and discovered its potential anti-inflammatory effects. This study aimed to investigate the anti-inflammatory effect of corilagin isolated from Euryale ferox Salisb shell. (2) Methods: We predict the anti-inflammatory mechanism by pharmacology. LPS was added to 264.7 cell medium to induce an inflammatory state, and the safe action range of corilagin was screened using CCK-8. The Griess method was used to determine NO content. The presence of TNF-α, IL-6, IL-1β, and IL-10 was determined by ELISA to evaluate the effect of corilagin on the secretion of inflammatory factors, while that of reactive oxygen species was detected by flow cytometry. The gene expression levels of TNF-α, IL-6, COX-2, and iNOS were determined using qRT-PCR. qRT-PCR and Western blot were used to detect the mRNA and expression of target genes in the network pharmacologic prediction pathway. (3) Results: Network pharmacology analysis revealed that the anti-inflammatory effect of corilagin may be related to MAPK and TOLL-like receptor signaling pathways. The results demonstrated the presence of an anti-inflammatory effect, as indicated by the reduction in the level of NO, TNF-α, IL-6, IL-1β, IL-10, and ROS in Raw264.7 cells induced by LPS. The results suggest that corilagin reduced the expression of TNF-α, IL-6, COX-2, and iNOS genes in Raw264.7 cells induced by LPS. The downregulation of the phosphorylation of IκB-α protein related to the toll-like receptor signaling pathway and upregulation of the phosphorylation of key proteins in the MAPK signaling pathway, P65 and JNK, resulted in reduced tolerance toward lipopolysaccharide, allowing for the exertion of the immune response. (4) Conclusions: The results demonstrate the significant anti-inflammatory effect of corilagin from Euryale ferox Salisb shell. This compound regulates the tolerance state of macrophages toward lipopolysaccharide through the NF-κB signaling pathway and plays an immunoregulatory role. The compound also regulates the expression of iNOS through the MAPK signaling pathway, thereby alleviating the cell damage caused by excessive NO release.

Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy?

Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here.

Human leukocyte antigen antibodies and leukocyte antigen/killer-cell immunoglobulin-like receptor genes are important in transplant immunology in the liver

Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance, which is described by eventual imbalances or deregulation in the balance of cytokines, mediators, effectors, and regulatory cells in the complex milieu of the liver. In this section, we will comment on the importance of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor (KIR) genotypes in the evolution of liver transplantation. Thus, HLA compatibility, viral infections, and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival. There have been reports of increased risk of acute and chronic rejection with ductopenia, faster graft fibrosis, biliary problems, poorer survival, and even de novo autoimmune hepatitis when DSAs are present in the recipient. Higher mean fluorescence intensity (MFI) values of the DSAs and smaller graft size were associated with poorer patient outcomes, implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods, according to the investigators. Similarly, in a combined kidney-liver transplant, a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment. The renal graft was lost owing to antibody-mediated rejection (AMR). The HLA antigens expressed by the transplanted liver graft influenced antibody elimination. Pathologists are increasingly diagnosing AMR in liver transplants, and desensitization therapy has even been employed in situations of AMR, particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex. In conclusion, after revealing the negative impacts of DSAs with high MFI, pretransplant virtual crossmatch techniques may be appropriate to improve evolution; however, they may extend cold ischemia periods by requiring the donor to be typed.

Restoring Balance: Immune Tolerance in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic musculoskeletal disease where immune dysregulation and subsequent autoimmunity induce significant synovial joint inflammation and damage, causing pain and disability. RA disease onset is promoted through multifaceted interactions between genetic and environmental risk factors. However, the mechanisms of disease onset are not completely understood and disease-specific treatments are yet to be developed. Current RA treatments include nonspecific disease-modifying antirheumatic drugs (DMARDs) that suppress destructive immune responses and prevent damage. However, DMARDs are not curative, and relapses are common, necessitating lifelong therapy in most patients. Additionally, DMARD-induced systemic immunosuppression increases the risk of serious infections and malignancies. Herein, we review the current understanding of RA disease pathogenesis, with a focus on T and B cell immune tolerance breakdown, and discuss the development of antigen-specific RA therapeutics that aim to restore a state of immune tolerance, with the potential for disease prevention and reduction of treatment-associated adverse effects.

Inhibition of specific signaling pathways rather than epigenetic silencing of effector genes is the leading mechanism of innate tolerance.

Macrophages activated through a pattern-recognition receptor (PRR) enter a transient state of tolerance characterized by diminished responsiveness to restimulation of the same receptor. Signaling-based and epigenetic mechanisms are invoked to explain this innate tolerance. However, these two groups of mechanisms should result in different outcomes. The epigenetic scenario (silencing of effector genes) predicts that activation of a PRR should broadly cross-tolerize to agonists of unrelated PRRs, whereas in the signaling-based scenario (inhibition of signaling pathways downstream of specific PRRs), cross-tolerization should occur only between agonists utilizing the same PRR and/or signaling pathway. Also, the so-called non-tolerizeable genes have been described, which acquire distinct epigenetic marks and increased responsiveness to rechallenge with the same agonist. The existence of such genes is well explained by epigenetic mechanisms but difficult to explain solely by signaling mechanisms. To evaluate contribution of signaling and epigenetic mechanisms to innate tolerance, we tolerized human macrophages with agonists of TLR4 or NOD1 receptors, which signal via distinct pathways, and assessed responses of tolerized cells to homologous restimulation and to cross-stimulation using different signaling, metabolic and transcriptomic read-outs. We developed a transcriptomics-based approach to distinguish responses to secondary stimulation from continuing responses to primary stimulation. We found that macrophages tolerized with a NOD1 agonist lack responses to homologous restimulation, whereas LPS-tolerized macrophages partially retain the ability to activate NF-κB pathway upon LPS rechallenge, which allows to sustain low-level expression of a subset of pro-inflammatory genes. Contributing to LPS tolerance is blockade of signaling pathways required for IFN-β production, resulting in 'pseudo-tolerization' of IFN-regulated genes. Many genes in NOD1- or TLR4-tolerized macrophages are upregulated as the result of primary stimulation (due to continuing transcription and/or high mRNA stability), but do not respond to homologous restimulation. Hyperresponsiveness of genes to homologous rechallenge is a rare and inconsistent phenomenon. However, most genes that have become unresponsive to homologous stimuli show unchanged or elevated responses to agonists of PRRs signaling via distinct pathways. Thus, inhibition of specific signaling pathways rather than epigenetic silencing is the dominant mechanism of innate tolerance.

Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.

Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma.

One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.

Low-overhead code concatenation approaches for universal quantum computation

Fault-tolerant quantum circuit design can be done by using a set of transversal gates. However, as there is no quantum error correction code with a universal set of transversal gates, several approaches have been proposed which, in combination of transversal gates, make universal fault-tolerant quantum computation possible. Magic state distillation, gauge fixing, code switching, code concatenation and pieceable fault tolerance are well-known examples of such approaches. However, the overhead of these approaches is one of the main bottlenecks for large-scale quantum computation. In this paper, two approaches for universal fault-tolerant quantum computation, mainly based on code concatenation, are proposed. The first approach combines the code concatenation approach with code switching, pieceable fault tolerance or magic state distillation and the second approach extends the nonuniformity of the concatenated codes by allowing to apply CNOT gates between different codes. The proposed approaches outperform the code concatenation approach in terms of both number of qubits and code distance and have also significantly less resource overhead than magic state distillation. This is achieved at the cost of reducing the effective distance of the concatenated code for implementing non-transversal gates.