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The present study examined the pathogenesis of interstitial inflammation and fibrosis in antihypertensively treated rats with two-kidney, one-clip hypertension. Hypertensive rats were randomized into four groups: no treatment and moderate, intermediate, and intensified lowering of blood pressure with increasing doses of a vasopeptidase inhibitor for 6 wk. The vasopeptidase inhibitor dose dependently lowered blood pressure. The tubulointerstitial damage was accompanied by a diffuse infiltration of mononuclear cells and circumscript mononuclear inflammatory cell cluster formation consisting mainly of T cells and to a lesser degree of macrophages and B cells. Real-time PCR analyses showed a dose-dependent induction of MCP-1 and the Th1-type chemokines IP10 and Mig as well as their receptor CXCR3 and the Th1 cytokine IFN-[gamma]. In situ hybridization and laser microdissection revealed a strong expression of these Th1-associated transcripts in the clusters and, in the case of MCP-1, also diffusely in the interstitium. The inflammation was accompanied by the appearance of myofibroblasts and synthesis of the fibrogenic factor plasminogen activator inhibitor-1 as well as the collagenase matrix metalloproteinase-2, leading to collagen I upregulation and interstitial scarring. No inflammation or fibrosis was found in normotensive rats treated with the vasopeptidase inhibitor. The renal injury in the clipped kidney is accompanied by compartment-specific chemokine expression and cell cluster formation of Th1 specificity associated with upregulation of fibrogenic proteins and matrix metalloproteinases. These findings suggest that the Th1 chemokines IP10 and Mig as well as their receptor CXCR3 are potential targets for therapeutic interventions in ischemic nephropathy. vasopeptidase inhibition; chemokines; Th1 response; acute renal failure; matrix metalloproteinases; MCP-1; IP10; Mig; renovascular hypertension

The volume expansion behavior of low-density polypropylene foams in extrusion is investigated in this paper. Since escape of blowing agent from the foam would cause the foam to contract, and to have low expansion, efforts were made to prevent gas loss during foaming. The basic strategies to the promotion of a large volume expansion ratio are: to use a branched material for preventing cell coalescence; to use a long-chain blowing agent with low diffusivity; to lower the melt temperature for decreasing gas loss during expansion; and to optimize the processing conditions in the die for avoiding too-rapid crystallization. Use of a branched polypropylene resin was required to achieve large volume expansion because prevention of cell coalescence will retard gas loss from the extruded foam to the environment. The foam morphologies of linear and branched polypropylene materials at various processing temperatures were studied using a single-screw tandem foam extrusion system and their volume expansion behaviors were c ompared. Ultra low-density, fine-celled polypropylene foams with very high expansion ratio up to 90-fold were successfully produced from the branched polypropylene resins., INTRODUCTION Thermoplastic foams possess a cellular structure create y the expansion of blowing agent. This internal structure provides unique properties that enable the foamed plastics to be used effectively for [...]

Etherified melamine resins are well known from the lacquer and paint industry. Up to now, important characterization in terms of composition and structure has been a time-consuming procedure. Now, fast analysis can also be achieved by use of 13C nuclear magnetic resonance spectroscopy. A special polarization transfer technique was applied to overcome the inherent low signal/noise ratio of 13C NMR spectra. The melamine content of the resin was determined by combustion analysis. This combination of methods allows for fast resin analysis with accuracy as yet unmatched and shows good correlation with established techniques. [ABSTRACT FROM AUTHOR]

Objective: The infiltration of inflammatory cells into renal tissue, mainly T cells and monocytes, is a typical feature of various renal diseases affecting the endothelium such as glomerulonephritis, thrombotic angiopathies, allogaft rejection and vasculitis. Chemokines are the chemotactic cytokines considered to be the main regulators of leukocyte trafficking under inflammatory conditions. The aim of our study was to analyze the expression and function of the chemokine IP-10/CXCL10 (acting via CXCR3 on activated T cells) in a rat model of renal microvascular endothelial injury. Methods: Renal microvascular endothelial injury was induced in rats by selective renal artery perfusion with anti-endothelial-antibody (Kidney Int 97, Johnson et al). Chemokine expression (Real time-PCR and in situ hybridization), T cell and monocyte infiltration (immunohistochemistry and FACS analysis) and serum creatinine/urea levels were assessed 24 h and 4 days after disease induction. To analyze the functional role of IP-10/CXCL10, rats were treated with a characterized neutralizing anti IP-10 antibody following induction of the endothelial injury. Results: Induction of microvascular endothelial injury increased renal IP-10/CXCL10 expression at 24 h (117-fold) and 4 days (5-fold). In situ hybridization revealed that IP-10/CXCL10 RNA is selectively expressed in the tubulointerstitial area (mainly by endothelial cells), co-localizing with infiltrating T cells. Treatment with a neutralizing anti IP-10/CXCL10 antibody significantly reduced the number of infiltrating tubulointerstitial T cells, serum creatinine and urea level. No significant glomerular IP-10/CXCL10 expression and T cell infiltration was detectable. Monocyte recruitment was not affected by anti IP-10/CXCL10 treatment, demonstrating a predominant role of this chemokine in tubulointerstitial T cell recruitment. Conclusions: Our findings demonstrate that microvascular renal injury leads to the tubulointerstitial expression of IP-10/CXCL10. The data provide strong evidence that a IP-10/CXCL10 mediated T cell recruitment is of functional importance in this model of microvascular injury. [ABSTRACT FROM AUTHOR]

Objective: Recent studies showed a crucial role for B cells in acute renal allograft rejection. It remains largely unknown, however, which mechanisms lead to the B cell recruitment into the allograft. The chemokine BCA-1/CXCL13 and its corresponding receptor CXCR5 play a central role in B cell trafficking to secondary lymphatic tissue. We therefore investigated the potential role of BCA-1/ CXCL13 and CXCR5 in formation of B cell clusters in renal transplant rejection. Methods: Serial immunohistochemical staining for BCA-1/ CXCL13, CXCR5 and CD20 was carried out in biopsies of 23 patients obtained between day 4 and day 9 after renal transplantation. Intragraft mRNA expression of BCA-1/CXCL13 was assessed by real time PCR analysis. Results: Of 23 kidney biopsies routinely obtained between days 4 and 9 after renal transplantation, 13 revealed an acute rejection. Four of these patients showed a substantial infiltration of the transplant with cluster forming B cells. By immunohistochemistry BCA-1/ CXCL13 and the corresponding receptor CXCR5 were exclusively detected in areas of B cell clusters. Intrarenal BCA-1/CXCL13 mRNA expression was 27-fold higher in transplants with B cell clusters compared to rejecting allografts without B cell accumulation (p = 0.011). Conclusions: We describe a striking co-localization of BCA-1/ CXCL13 expression with CXCR5 and CD20 positive B cells in renal transplants undergoing rejection. This is the first study demonstrating a potential role of BCA-1/CXCL13 and its specific receptor CXCR5 in recruitment of B cells in renal allograft rejection. [ABSTRACT FROM AUTHOR]

Autoimmunity against the Goodpasture antigen [alpha]3IV-NC1 results in antiglomerular basement membrane glomerulonephritis. Although antibodies are central to the pathogenesis, there is good evidence for the participation of T cells in this disease. To define the contribution of T cells, we used the model of experimental autoimmune glomerulonephritis. Immunization of DBA/1 mice with [alpha]3IV-NC1 resulted in proteinuria, a biphasic course of the disease, and an eventual loss of kidney function. In the initial phase, the mice developed an [alpha]3IV-NC1-specific IgG response, had IgG deposition along the glomerular basement membrane, and steadily increased proteinuria, but only marginal signs of inflammation with limited leukocyte infiltration. After 9-13 weeks, mice proceeded to develop crescentic glomerulonephritis, extensive tubulointerstitial damage, and massive macrophage infiltration. T-cell infiltration was less pronounced, mostly confined to the interstitium, and T cells displayed an activated phenotype with a significant fraction of Th1 or Th17 CD4(+) T cells. Close examination revealed the presence of autoreactive T cells producing IFN[gamma] upon restimulation with [alpha]3IV-NC1. Thus, our results suggest that accumulation of effector T cells, including autoreactive T cells, represents a critical step in the progression from mild glomerulonephritis, with limited glomerular damage, to severe crescentic glomerulonephritis accompanied by tubulointerstitial inflammation and loss of kidney function. [ABSTRACT FROM AUTHOR]

Crescentic glomerulonephritis is mediated by inappropriate humoral and cellular immune responses toward self-antigens that may result from defects in central and peripheral tolerance. Evidence now suggests that regulatory T cells (Tregs) may be of pathophysiological importance in proliferative and crescentic forms of glomerulonephritis. To analyze the role of endogenous Tregs in a T cell-dependent glomerulonephritis model of nephrotoxic nephritis, we used 'depletion of regulatory T cell' (DEREG) mice that express the diphtheria toxin receptor under control of the FoxP3 (forkhead box P3) gene promoter. Toxin injection into these mice efficiently depleted renal and splenic FoxP3(+) Treg cells as determined by fluorescent-activated cell sorting (FACS) and immunohistochemical analyses. Treg depletion exacerbated systemic and renal interferon-γ (IFNγ) expression and increased recruitment of IFNγ-producing Th1 cells into the kidney without an effect on the Th17 immune response. The enhanced Th1 response, following Treg cell depletion, was associated with an aggravated course of glomerulonephritis as measured by glomerular crescent formation. Thus, our results establish the functional importance of endogenous Tregs in the control of a significantly enhanced systemic and renal Th1 immune response in experimental glomerulonephritis. [ABSTRACT FROM AUTHOR]

The evaluation of compound-target interactions (CTIs) is at the heart of drug discovery efforts. Given the substantial time and monetary costs of classical experimental screening, significant efforts have been dedicated to develop deep learning-based models that can accurately predict CTIs. A comprehensive comparison of these models on a large, curated CTI dataset is, however, still lacking. Here, we perform an in-depth comparison of 12 state-of-the-art deep learning architectures that use different protein and compound representations. The models were selected for their reported performance and architectures. To reliably compare model performance, we curated over 300 thousand binding and non-binding CTIs and established several gold-standard datasets of varying size and information. Based on our findings, DeepConv-DTI consistently outperforms other models in CTI prediction performance across the majority of datasets. It achieves an MCC of 0.6 or higher for most of the datasets and is one of the fastest models in training and inference. These results indicate that utilizing convolutional-based windows as in DeepConv-DTI to traverse trainable embeddings is a highly effective approach for capturing informative protein features. We also observed that physicochemical embeddings of targets increased model performance. We therefore modified DeepConv-DTI to include normalized physicochemical properties, which resulted in the overall best performing model Phys-DeepConv-DTI. This work highlights how the systematic evaluation of input features of compounds and targets, as well as their corresponding neural network architectures, can serve as a roadmap for the future development of improved CTI models.Scientific contributionThis work features comprehensive CTI datasets to allow for the objective comparison and benchmarking of CTI prediction algorithms. Based on this dataset, we gained insights into which embeddings of compounds and targets and which deep learning-based algorithms perform best, providing a blueprint for the future development of CTI algorithms. Using the insights gained from this screen, we provide a novel CTI algorithm with state-of-the-art performance., (© 2024. The Author(s).)

Th17 cells play crucial roles in host defense and the pathogenesis of autoimmune diseases in the skin. While their differentiation mechanisms have been extensively studied, the origin of skin Th17 cells remains unclear. In this study, we analyzed single-cell RNA-sequencing data and identify the presence of Th17 cells in the human thymus. Thymic Th17 cells were characterized by high expression levels of Sphingosine-1-Phosphate Receptor 1 (S1PR1), a receptor crucial for T cell egress from lymphoid tissues. In mice, Th17 cell-specific knockout of S1pr1 resulted in the accumulation of Th17 cells in the thymus and a corresponding decrease in their numbers in the skin. Th17 cells that accumulated in the thymus exhibited a lower IL-17A production capacity compared to those in the skin, indicating that the local environment in the skin is important for maintaining the Th17 cell phenotype. Additionally, using a murine psoriasis model, we demonstrated that Th17 cell-specific knockout of S1pr1 reduced their migration to the inflamed skin, thereby ameliorating disease progression. Collectively, our data suggest that S1PR1 mediates Th17 cell migration from the thymus to the skin, thereby modulating their functional engagement in both homeostatic and inflammatory conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Engesser, Wang, Kapffer, Kaffke, Peters, Paust, Geissen, Krebs, Panzer and Asada.)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4 + and CD8 + T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials., (© 2024. The Author(s).)

Immune-mediated kidney diseases, including glomerulonephritis (GN), represent a diverse spectrum of disorders characterized by inflammation within the glomerulus and other renal compartments. Despite recent advances, the immunopathogenesis of these diseases remains incompletely understood. Current therapeutic approaches based on nonspecific immunosuppression often result in suboptimal outcomes and significant side effects, highlighting the need for tailored interventions. The complexity of the immune system extends beyond classical T-cell immunity, with the emergence of unconventional T cells - γδ T cells, NKT cells, and MAIT cells - that exhibit a semi-invariant nature and unique functions that bridge innate and adaptive immunity. γδ T cells exhibit unique homing and activation mechanisms and respond to different ligands, implying a multifaceted role in immune regulation. The understanding of γδ T-cell involvement in kidney disease lags behind conventional T-cell research. However, advances in immune cell analysis technologies offer promising avenues for elucidating their precise functions. This review synthesizes the current knowledge on γδ T cells in renal diseases, explores potential therapeutic strategies, and presents a roadmap for future research directions., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)