Biology subjects

Toldo, S.

Publications and source records attributed to Toldo, S..

6 recordsLinked to original sources

bioRxiv2026

Treatment of murine autoimmune myocarditis with a novel monoclonal antibody that targets multiple inflammatory pathways

Severe forms of inflammation-induced acute and chronic myocarditis have a poor prognosis. Promising therapeutic efforts focused on monoclonal antibodies (mAbs) inhibiting inflammation-inducing molecules. However, most mAbs target only one or a limited number of such molecules. Since inflammation involves multiple redundant pathways, we postulated that an mAb inhibiting multiple inflammatory pathways would be a potent therapeutic agent. We initially tested the commercially available anti-natural killer (NK) cell mAb (anti-NK1.1), which binds a receptor expressed on NK cells and depletes them. Since NK cells are key cellular orchestrators of inflammation, by reducing their number, we aimed to inhibit multiple inflammatory pathways. Our initial studies demonstrated that administration of this antibody significantly improved myocardial outcomes in mouse models of acute myocardial infarction and of heart failure. Since NK1.1 is not expressed in human cells, we built on these promising preclinical results by developing a novel mAb targeting CD160 on human NK cells for evaluation as an immunosuppressive therapy. We found that the anti-CD160 mAb depletes both murine and human NK cells. We also found that, while CD160+ cells were largely present in the NK population, they also occurred among CD8+ and {gamma}/{delta} T cell subsets in human cells. Anti-CD160 therapy entirely prevented the deterioration of the myocardial function of mice with autoimmune-induced acute myocarditis. This outcome suggests our novel approach for inhibiting multiple inflammatory pathways may provide a potent strategy for improving outcomes of inflammation-driven myocarditis, as well as of other inflammation-driven diseases. Key PointsO_ST_ABSQuestionC_ST_ABSCan the depletion of CD160+ cells prevent autoimmune-induced myocarditis? FindingsIn this study we found that CD160 is expressed by mouse and human natural killer cells and other subtypes of cytotoxic T cells, and that a monoclonal antibody targeting CD160 depletes NK cells. In a preclinical model of experimental autoimmune myocarditis, administration of the anti-CD160 monoclonal antibody prevented myocardial dysfunction and systemic inflammation. MeaningOur results are compatible with the hypothesis that early autoimmune-induced myocardial dysfunction is promoted by CD160+ cells, which elevate inflammation-induced circulating factors (or factors released by tissue-resident cytotoxic immune cells) that cause myocardial dysfunction in the absence of myocardial necrosis or fibrosis, and further, that targeting CD160+cells with a mAb that depletes NK cells (and probably CD160 expressing cytotoxic T cells) entirely prevents the deterioration of myocardial function in such mice. This outcome suggests our novel approach for inhibiting multiple inflammatory pathways may provide a potent strategy for improving outcomes of inflammation-driven myocarditis, as well as of other inflammation-driven diseases.

systems biology↗

bioRxiv2025

INTERLEUKIN-18 AS A THERAPEUTIC TARGET FOR WESTERN DIET-INDUCED CARDIOMYOPATHY

BackgroundA diet high in saturated fats and sugars (Western diet-WD) promotes obesity and left ventricular dysfunction in the mouse, which is, at least in part, mediated by pro-inflammatory cytokine Interleukin-18 (IL-18). Therefore, we hypothesized that a blocking recombinant-murine IL-18 binding protein (IL-18BP) would rescue cardiac function in WD-fed mice. MethodsIn this 9-week study, 10-week-old adult C57BL/6J mice were assigned to standard diet (SD) or a WD. After 7 weeks of WD feeding, the mice were assigned to two groups: WD+IL-18BP (0.5 mg/kg daily, intraperitoneal injections) or WD control for the last 2 weeks of the study. Food intake, body weight, and glucose tolerance were assessed. Cardiac systolic and diastolic function were measured by Doppler echocardiography at baseline, 5 weeks, and 9 weeks. IL-18 plasma levels were quantified with ELISA. ResultsWD induced a significant increase in body weight, significantly worsened glucose tolerance, and significantly increased (worsening) in diastolic function (isovolumetric relaxation time -IRT- and myocardial performance index -MPI-) compared to SD. Rescue with IL-18BP in WD-fed mice resulted in a significant improvement in IRT and MPI, without significant changes in food intake, weight gain, or glucose tolerance. ConclusionsIL-18BP rescued cardiac function in mice with WD-induced diastolic dysfunction, independent of weight gain and glucose tolerance. These results confirm the central and independent role of IL-18 in cardiac dysfunction associated with diet-induced obesity.

physiology↗

bioRxiv2025

UNCONVENTIONAL INTERLEUKIN-1 SIGNALING IN CARDIAC DYSFUNCTION

Interleukin-1{beta} (IL-1{beta}) is an apical pro-inflammatory cytokine that has also been shown to negatively modulate cardiac contractility. Whether IL-1{beta} effects on systemic inflammation and cardiac function are intertwined and associated with each other, or whether they are independent of each other, is unknown. An unconventional signaling of the IL-1 receptor type I through the phosphoinositide-3 kinase{gamma} (PI3K{gamma}), at least in part independent of the proinflammatory signaling, has been characterized in inflammation and cancer. We hypothesized that IL-1{beta} would increase the expression of PI3K p110{gamma} in cardiomyocytes, which in turn results in selective induction of p87 co-signaling and cardiac dysfunction through a scaffolding function on phosphodiesterase 3B (PDE3B). Using genetically modified mice, we show that a kinase-independent PI3K p110{gamma} mechanism mediates IL-1-induced cardiac dysfunction. This may have compelling implications for the understanding and treatment of heart failure with reduced ejection fraction.

immunology↗

bioRxiv2025

Orally Delivered Milk-Derived Nanovesicles Loaded with Connexin 43 Peptides forTargeted Cardiac Ischemia-Reperfusion Therapy

Extracellular vesicles have emerged as promising nanocarriers for targeted drug delivery, but their therapeutic potential is limited by challenges related to administration route, loading, targeted delivery and production at scale. Here, we report an innovative approach for targeted delivery of therapeutic peptides to injured tissues using milk-derived small extracellular vesicles (mEVs) as an abundant, safe, orally administrable nanoplatform. We demonstrate that a sub-population of mEVs naturally contain Connexin 43 (Cx43) and its Carboxyl-Terminal (CT) polypeptides, which have been shown to play crucial roles in wound healing and tissue repair. Leveraging this intrinsic property, we developed an esterification method to efficiently and uniformly load mEVs with enhanced levels of an exogenous Cx43 CT peptide (CT11 - RPRPDDLEI), as assessed by flow cytometry-based vesicle quantification and mass spectrometry. These engineered mEVs exhibited remarkable injury targeting capabilities, with > 30-fold increases in uptake by injured cells compared to non-wounded cells in vitro and preferential accumulation in wounded tissues in vivo. Notably, CT11-loaded mEVs orally administered after myocardial infarction reduced infarct size by >60% and preserved heart function in a mouse model of ischemia-reperfusion injury. This study represents a significant advance in nanomedicine, demonstrating the utilization of naturally occurring milk-derived extracellular vesicles as an oral delivery system for therapeutic peptides, achieving unprecedented targeting efficiency and efficacy in the treatment of myocardial ischemia-reperfusion injury.

bioengineering↗

bioRxiv2024

Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques

Precise quantification of myocardial infarction is crucial for evaluating the therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and the isolation and quantification of diffuse fibrosis in the heart. Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Massons trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue for the four staining techniques. Notably, the infarct region on a H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise in the infarct quantification. Additionally, our program can isolate and quantify the diffuse fibrotic elements from an MTS-stained cardiac section, which suggested the algorithms potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. In conclusion, we demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as the diffuse and patchy fibrosis in MTS-stained cardiac tissues.

pathology↗

bioRxiv2019

Transcriptomic learning for digital pathology

Deep learning methods for digital pathology analysis have proved an effective way to address multiple clinical questions, from diagnosis to prognosis and even to prediction of treatment outcomes. They have also recently been used to predict gene mutations from pathology images, but no comprehensive evaluation of their potential for extracting molecular features from histology slides has yet been performed. We propose a novel approach based on the integration of multiple data modes, and show that our deep learning model, HE2RNA, can be trained to systematically predict RNA-Seq profiles from whole-slide images alone, without the need for expert annotation. HE2RNA is interpretable by design, opening up new opportunities for virtual staining. In fact, it provides virtual spatialization of gene expression, as validated by double-staining on an independent dataset. Moreover, the transcriptomic representation learned by HE2RNA can be transferred to improve predictive performance for other tasks, particularly for small datasets. As an example of a task with direct clinical impact, we studied the prediction of microsatellite instability from hematoxylin & eosin stained images and our results show that better performance can be achieved in this setting.

bioinformatics↗