An IL-2 mutein increases regulatory T cell suppression of dendritic cells via IL-10 and CTLA-4 to promote T cell anergy.

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and T cell receptor-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface major histocompatibility complex class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 co-stimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes, resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

Identifying key monitoring areas for tree insect pest risks in China under climate change.

Climate change can exacerbate pest population growth, posing significant threats to ecosystem functions and services, social development, and food security. Risk assessment is a valuable tool for effective pest management that identifies potential pest expansion and ecosystem dispersal patterns. We applied a habitat suitability model coupled with priority protection planning software to determine key monitoring areas (KMA) for tree insect pest risks under climate change and used forest ecoregions and nature reserves to assess the ecological risk of insect pest invasion. Finally, we collated the prevention and control measures for reducing future pest invasions. The KMA for tree insect pests in our current and future climate is mainly concentrated in eastern and southern China. However, with climate change, the KMA gradually expands from southeastern to northeastern China. In the current and future climate scenarios, ecoregions requiring high monitoring levels were restricted to the eastern and southern coastal areas of China, and nature reserves requiring the highest monitoring levels were mainly distributed in southeastern China. Tree insect pest invasion assessment using ecoregions and nature reserves identified that future climates increase the risk of pest invasions in forest ecoregions and nature reserves, especially in northeastern China. The increased risk and severity of tree insect pest invasions require implementing monitoring and preventative measures in these areas. We effectively assessed the pest invasion risks using forest ecoregions and nature reserves under climate change. Our assessments suggest that monitoring and early prevention should focus on southeastern and northeastern China.

Linear relationships between aboveground biomass and plant species diversity during the initial stage of degraded grassland restoration projects.

The relationship between aboveground biomass and plant diversity has been extensively examined to understand the role of biodiversity in ecosystem functions and services. Degraded grassland restoration projects can enhance carbon sequestration. However, the relationship between biomass and diversity remains one of the most actively debated topics regarding grassland ecosystems in degraded grassland restoration projects. We speculated that establishing the linear relationships between aboveground biomass and plant species diversity could contribute to enhancing the efficacy of degraded grassland restoration projects. This study sought to determine whether these relationships were linear during the initial stages of the restoration projects of degraded grasslands in Xing'an League, China. The investigations were based on an examination of seventy-six 1 × 1 m2 plots distributed among 15 areas in which the degraded grassland was at the initial stages of restoration. To quantify the species diversity of the degraded grassland communities, we used the species richness, Shannon-Wiener, inverse Simpson's reciprocal, and Pielou's evenness indices. Our analyses revealed that aboveground biomass had clear positive linear relationships with species richness during the initial stages of degraded grassland restoration. However, there were less pronounced associations with species diversity as assessed using the Shannon and inverse Simpson indices, based on regression models. Furthermore, weed biomass was found to have significant negative effects on species richness and Pielou's evenness. The weak linear relationship between aboveground biomass and species richness could be ascribed to an increase in weed biomass. We concluded that aboveground biomass and plant species diversity could be enhanced during the initial stages of degraded grassland restoration projects and suggest that the extent of weed biomass could serve as a key indicator of the efficacy of restoration from the perspective of plant species diversity and aboveground biomass in carbon sequestration projects.

Vitamin D nutritional status in early pregnancy and its relationship with periconceptional multiple micronutrients supplementation.

BACKGROUND AND OBJECTIVES: To assess the vitamin D nutritional status (VDN) of pregnant women in early pregnancy and investigate the effects of periconceptional supplementation with multiple micronutrients (MMs) on this status. METHODS AND STUDY DESIGN: Data were taken from the Pregnancy Health Care System and Hospital Information System in 2018 in Beijing. Vitamin D nutritional status in early pregnancy was evaluated among 4,978 pregnant women, and 4,540 women who took folic acid only (FA) or multiple mi-cronutrients supplements (MM) during the periconceptional period, were include to estimate the associations between periconceptional supplementation with MM and prevalence of vitamin D deficiency or insufficiency with logistic regression model. RESULTS: The mean early-pregnancy vitamin D concentration was 18.6 (±7.5) ng/mL, and the rates of deficiency and insufficiency were 31.6% and 60.5%, respectively. Compared to the FA group, the adjusted odds ratio (aOR, 95%confidence interval, CI) for insufficiency or deficiency of the MM group were 0.25(0.18-0.34), and the aOR (95%CI) for deficiency of the MM group were 0.17 (0.12-0.23). Women who took MMs for a longer period of time, at higher frequencies, and with higher compliance scores had lower rates of deficiency and insufficiency. In winter, spring, and autumn, taking MMs could reduce deficiency by about 70%; in summer, there was little effect. CONCLUSIONS: Among women in Beijing, serum concentrations of vitamin D in early pregnancy are relatively low, and the rates of deficiency and insufficiency are high. Taking MMs during the periconceptional period could improve this situation.

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells.

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

A dataset of functional traits for compound pinnate leaves of plants in the Huangshui River Valley of Qinghai Province, China.

Background: Here, we present data collected from the Qinghai-Tibet Plateau that describes the variation of leaf functional traits across 32 plant species and could be used to investigate plant community functioning and predict the impact of climate change on biogeochemical cycles. The sampling area is located in Huangshui River Valley, in the southeast of Qinghai Province, China (36° 19' to 36° 53' N, 100° 59' to 102° 48' E). The area contains an alpine meadow typical of the Qinghai-Tibet Plateau. New information: This dataset includes field survey data on the functional properties of compound leaves from herbaceous species in the Huangshui River Basin of Qinghai Province, China, at altitudes from 1800 m to 4000 m in the summer of 2021. Data were collected from 326 plots, including 646 data points of compound leaf plants, spanning 32 compound leaf plant species belonging to 14 genera and four families. The study species were chosen from 47 families, 165 genera and 336 species present in the plots and all compound leaf plants were chosen within each plot. We picked the parts containing leaves, petioles and rachis from the study plants and separated the leaves from the plants. The cut compound leaf part was a leaflet, while the petiole and rachis were linear elements. The dataset includes information about the leaflet trait variation (i.e. leaflet area, leaflet dry mass, specific leaflet area and leaflet nitrogen content per unit dry mass) and linear elements' biomass and nitrogen content per unit dry mass (i.e. both petiole and rachis) of 646 compound leaves. This dataset can be used to analyse the evolution of leaf traits and the basic functioning of ecosystems. Moreover, the dataset provides an important basis for studying the species distribution and protection of biodiversity of the Qinghai-Tibet Plateau and evaluating ecosystem services. These data also support the high-quality development of the Yellow River Basin and have empirical and practical value for alpine biodiversity protection and ecosystem management.

IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation.

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.

Complete chloroplast genome data for Mimosa diplotricha and Mimosa diplotricha var. inermis from China.

Mimosa diplotricha (Fabaceae) and Mimosa diplotricha var. inermis are invasive taxa introduced in the Chinese mainland in the 19th century. M. diplotricha has been listed in the list of highly invasive species in China, which has seriously endangered the growth and reproduction of local species. As a poisonous plant, M. diplotricha var. inermis, a variant of M. diplotricha, will also endanger the safety of animals. We report the complete chloroplast genome sequence of M. diplotricha and M. diplotricha var. inermis. The chloroplast genome of M. diplotricha is 164,450 bp long and the chloroplast genome of M. diplotricha var. inermis is 164,445 bp long. Both M. diplotricha and M. diplotricha var. inermis contain a large single-copy region (LSC) of 89,807 bp and a small single-copy (SSC) region of 18,728 bp. The overall GC content of the two species is both 37.45%. A total of 84 genes were annotated in the two species, namely 54 protein-coding genes, 29 tRNA genes, and one rRNA gene. The phylogenetic tree based on the chloroplast genome of 22 related species showed that Mimosa diplotricha var. inermis is most closely related to M. diplotricha, while the latter clade is sister to Mimosa pudica, Parkia javanica, Faidherbia albida, and Acacia puncticulata. Our data provide a theoretical basis for the molecular identification, genetic relationships, and invasion risk monitoring of M. diplotricha and M. diplotricha var. inermis.

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.

Neural progenitor cells derived from fibroblasts induced by small molecule compounds under hypoxia for treatment of Parkinson's disease in rats.

Neural progenitor cells (NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox (VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR (0.5 mM valproic acid, 3 µM CHIR99021, and 1 µM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition (5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6 (Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs (ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson's disease.

Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity.

Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous. Here we probe the relative roles of CD28 and IL-2 in maintaining Treg. We find provision of IL-2 counteracts the regulatory T cell loss induced by costimulation blockade while minimally affecting the conventional T cell compartment. These data suggest that combining costimulation blockade with IL-2 treatment may selectively impair effector T cell responses while maintaining regulatory T cells. Using a mouse model of autoimmune diabetes, we show combined therapy supports regulatory T cell homeostasis and protects from disease. These findings are recapitulated in humanised mice using clinically relevant reagents and provide an exemplar for rational use of a second immunotherapy to offset known limitations of the first.

[VCR, a Small Molecule Compound, Induces Reprogramming of Rat Fibroblasts into Neural Progenitor Cells under Hypoxic Condition].

Objective: To explore for a protocol for reprogramming rat embryonic fibroblasts (REFs) under hypoxic conditions (5% O 2) to form chemically induced rat neural progenitor cells (ciRNPCs). Methods: The reprogramming of REFs into ciNPCs was done in two stages. The first stage involved chemical induction to generate intermediate cells. The REFs were cultured in KSR medium containing valproic acid, CHIR99021, and RepSox (VCR) and 10000 U/mL leukemia inhibitory factor (LIF) for 15 days, under a physiological hypoxic condition. The formation of dense cell colonies, i.e., intermediate cells, were observed. The second stage involved the specific induction of ciRNPCs. The induced intermediate cells were digested with trypsin, seeded on a low adhesion plate, and cultured under normoxic condition to form ciRNPCs neurospheres. Then, after CM-DiI cell-labeling, the ciRNPCs were stereotactically transplanted into the substantia nigra (SN) of rats. The survival, migration, and differentiation of ciRNPCs in the host brain were examined with immunofluorescence assays. Results: After induction under hypoxic condition for 5 to 10 days, a clear trend of cell aggregation was observed. Compact cell colonies were observed in REFs treated with VCR for 15 days under a hypoxic condition. Approximately 30 colonies emerged from 1×10 5 cells, and most colonies were positive for AP staining. Moreover, when these cells were cultured further in suspension, free-floating neurospheres formed and stained positive for neural progenitor cell (NPC) markers, including Nestin, Sox2 and Pax6. These ciRNPCs could differentiate into glial cells and neurons, and express neurite marker Tuj1 and astrocyte marker GFAP. Eight weeks after transplantation, the cells could differentiate into GFAP+ and Tuj1+ cells in the rat brain. Conclusion: Our study demonstrates that VCR, a small molecule compound, can directly induce, under a hypoxic condition, the reprogramming of REFs to form ciRNPCs with the potential to be induced for differentiation into glial cells and neurons in vivo and in vitro, laying the foundation for transplanting ciRNPCs to treat neurodegenerative diseases.

Development of novel polymorphic microsatellite markers for Picea brachytyla.

BACKGROUND: Picea brachytyla is a unique tree species in China. Due to being extensively exploited in the past, it is listed as Vulnerable in the IUCN Red List. It is mainly distributed across the Hengduan and Daba-Qinglin mountains and has been found in other areas including Sichuan Province and Qinghai Province, China. Microsatellites, or simple sequence repeats (SSRs), are widely used in correlational studies of genetic protection. Few markers have been developed for P. brachytyla because of the small number of trees and scholarly resources available for study. METHODS AND RESULTS: The genomic DNA of P. brachytyla was sequenced using the DNBSEQ platform, and unigenes were obtained after assembly and deredundancy. Of the 100 primer pairs screened, we isolated 10 useful microsatellite loci from P. brachytyla genes. The observed and expected heterozygosity values ranged from 0.173 (P24) to 0.788 (P79; mean 0.469) and 0.199 (P87) to 0.911 (P79; mean 0.700), respectively. Polymorphism-information content (PIC) ranged from 0.190 (P84) to 0.904 (P79; mean 0.666). Only P84 and P72 were in a Hardy-Weinberg equilibrium (P > 0.05) in the different P. brachytyla populations. All the levels of linkage disequilibrium (LD) were high for the 10 SSR loci indicating that there were no autocorrelations among the 10 SSR loci. CONCLUSIONS: The novel polymorphic microsatellite markers showed high polymorphism for P. brachytyla. These polymorphic microsatellites can provide a basis for future conservation and genetic research on this rare plant species.

Using Consensus Land Cover Data to Model Global Invasive Tree Species Distributions.

Invasive tree species threaten ecosystems, natural resources, and managed land worldwide. Land cover has been widely used as an environmental variable for predicting global invasive tree species distributions. Recent studies have shown that consensus land cover data can be an effective tool for species distribution modelling. In this paper, consensus land cover data were used as prediction variables to predict the distribution of the 11 most aggressive invasive tree species globally. We found that consensus land cover data could indeed contribute to modelling the distribution of invasive tree species. According to the contribution rate of land cover to the distribution of invasive tree species, we inferred that the cover classes of open water and evergreen broadleaf trees have strong explanatory power regarding the distribution of invasive tree species. Under consensus land cover changes, invasive tree species were mainly distributed near equatorial, tropical, and subtropical areas. In order to limit the damage caused by invasive tree species to global biodiversity, human life, safety, and the economy, strong measures must be implemented to prevent the further expansion of invasive tree species. We suggest the use of consensus land cover data to model global invasive tree species distributions, as this approach has strong potential to enhance the performance of species distribution modelling. Our study provides new insights into the risk assessment and management of invasive tree species globally.

Risk assessment of insect pest expansion in alpine ecosystems under climate change.

BACKGROUND: Growth in insect pest populations poses a significant threat to ecosystem functions and services, societal development, and food security in alpine regions under climate change. Risk assessments are important prioritization tools for pest management, which must be used to study insect pest expansion in alpine ecosystems under global warming. We used species distribution modeling to simulate the current and future distribution probabilities of 58 insect pest species in the Qinghai Province, China, based on a comprehensive field investigation. Subsequently, general linear modeling was used to explore the relationship between the distribution probability of these species and the damage caused by them. Finally, we assessed the ecological risk of insect pest expansion across different alpine ecosystems under climate change. RESULTS: Climate change could increase the distribution probabilities of insect pest species across different alpine ecosystems. However, the presence of insect pest species may not correspond to the damage occurrence in alpine ecosystems based on percent leaf loss, amount of stunting, and seedling death of their host species. Significant positive relationships between distribution probability and damage occurrence were found for several of the examined insect pest species. Insect pest expansion is likely to increase extensively in alpine ecosystems under increasing carbon dioxide (CO2 ) emission scenarios. CONCLUSION: The relationships between distribution probability and damage occurrence should be considered in species distribution modeling for risk assessment of insect pest expansion under climate change. Our study could improve the effectiveness of risk assessment of insect pest expansion under changing climate conditions. © 2021 Society of Chemical Industry.

Predicting clinical response to costimulation blockade in autoimmunity.

Curbing unwanted T cell responses by costimulation blockade has been a recognised immunosuppressive strategy for the last 15 years. However, our understanding of how best to deploy this intervention is still evolving. A key challenge has been the heterogeneity in the clinical response to costimulation blockade, and an inability to predict which individuals are likely to benefit most. Here, we discuss our recent findings based on the use of costimulation blockade in people with type 1 diabetes (T1D) and place them in the context of the current literature. We discuss how profiling follicular helper T cells (Tfh) in pre-treatment blood samples may have value in predicting which individuals are likely to benefit from costimulation blockade drugs such as abatacept.

Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.

Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.

MiR-559 targets GP73 to suppress proliferation and invasion of hepatocellular carcinoma in vitro.

Hepatocellular carcinoma (HCC) is one of the common malignant tumors with poor overall prognosis. As a tumor suppressor, the function of miR-559 in HCC is not clear. In this study, quantitative real-time PCR was carried out to measure the expression of miR-559 in HCC cell lines. The effects of miR-559 on HCC cell proliferation, migration, and invasion were evaluated through a series of functional assays. The mechanism through which miR-559 regulates HCC cells was investigated by dual-luciferase reporter assay and functional experiments. The results revealed that miR-559 expression was low in HCC cell lines. Upregulation of miR-559 suppressed HCC cell proliferation, migration, and invasion. Dual-luciferase reporter assay confirmed Golgi membrane protein 73 (GP73) as a target gene of miR-559. Moreover, miR-559 could negatively regulate GP73 expression in HCC cells. These results demonstrated that low-level expression of miR-559 was associated with HCC, and overexpression of miR-559 could inhibit HCC cell growth and invasion via targeting GP73.

Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN.

BACKGROUND: Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN. METHODS: We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis. RESULTS: All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses. CONCLUSIONS: Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.