Direct Gene Transfer with IP-10 Mutant Ameliorates Mouse CVB3-Induced Myocarditis by Blunting Th1 Immune Responses

Background: Myocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 (CVB3) being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, herein an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated. Methodology/Principal Findings: The depletion mutant pIP-10-AT, with an additional methionine after removal of the 5 N-terminal amino acids, was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection. Compared with vector or no treatment, pIP-10-AT treatment had significantly reduced heart/body weight ratio and serum CK-MB level, increased survival rate and improved heart histopathology, suggesting an ameliorated myocarditis. This therapeutic effect was not attributable to an enhanced viral clearance, but to a blunted Th1 immune response, as evidenced by significantly decreased splenic CD4 + /CD8 + IFN-c + T cell percentages and reduced myocardial Th1 cytokine levels. Conclusion/Significance: Our findings constitute the first preclinical data indicating that interfering in vivo IP-10 activit

Regulation of Endothelial Cell Adhesion Molecule Expression by Mast Cells, Macrophages, and Neutrophils

Leukocyte adhesion to the vascular endothelium and subsequent transendothelial migration play essential roles in the pathogenesis of cardiovascular diseases such as atherosclerosis. The leukocyte adhesion is mediated by localized activation of the endothelium through the action of inflammatory cytokines. The exact proinflammatory factors, however, that activate the endothelium and their cellular sources remain incompletely defined.Using bone marrow-derived mast cells from wild-type, Tnf(-/-), Ifng(-/-), Il6(-/-) mice, we demonstrated that all three of these pro-inflammatory cytokines from mast cells induced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin in murine heart endothelial cells (MHEC) at both mRNA and protein levels. Compared with TNF-α and IL6, IFN-γ appeared weaker in the induction of the mRNA levels, but at protein levels, both IL6 and IFN-γ were weaker inducers than TNF-α. Under physiological shear flow conditions, mast cell-derived TNF-α and IL6 were more potent than IFN-γ in activating MHEC and in promoting neutrophil adhesion. Similar observations were made when neutrophils or macrophages were used. Neutrophils and macrophages produced the same sets of pro-inflammatory cytokines as did mast cells to induce MHEC adhesion molecule expression, with the exception that macrophage-derived IFN-γ showed negligible effect in inducing VCAM-1 expression in MHEC.Mast cells, neutrophils, and macrophages release pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL6 that induce expression of adhesion molecules in endothelium and recruit of leukocytes, which is essential to the pathogenesis of vascular inflammatory diseases

Cardiotoxicity of immune checkpoint inhibitors

Cardiac toxicity after conventional antineoplastic drugs (eg, anthracyclines) has historically been a relevant issue. In addition, targeted therapies and biological molecules can also induce cardiotoxicity. Immune checkpoint inhibitors are a novel class of anticancer drugs, distinct from targeted or tumour type-specific therapies. Cancer immunotherapy with immune checkpoint blockers (ie, monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand (PD-L1)) has revolutionised the management of a wide variety of malignancies endowed with poor prognosis. These inhibitors unleash antitumour immunity, mediate cancer regression and improve the survival in a percentage of patients with different types of malignancies, but can also produce a wide spectrum of immune-related adverse events. Interestingly, PD-1 and PD-L1 are expressed in rodent and human cardiomyocytes, and early animal studies have demonstrated that CTLA-4 and PD-1 deletion can cause autoimmune myocarditis. Cardiac toxicity has largely been underestimated in recent reviews of toxicity of checkpoint inhibitors, but during the last years several cases of myocarditis and fatal heart failure have been reported in patients treated with checkpoint inhibitors alone and in combination. Here we describe the mechanisms of the most prominent checkpoint inhibitors, specifically ipilimumab (anti-CTLA-4, the godfather of checkpoint inhibitors) patient and monoclonal antibodies targeting PD-1 (eg, nivolumab, pembrolizumab) and PD-L1 (eg, atezolizumab). We also discuss what is known and what needs to be done about cardiotoxicity of checkpoint inhibitors in patients with cancer. Severe cardiovascular effects associated with checkpoint blockade introduce important issues for oncologists, cardiologists and immunologists

IL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells

Earlier, we have shown that GM-CSF-exposed CD8α− DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1β can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1β on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1β enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1β and IL-12 had only a modest effect on Foxp3− expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1β or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1β in promoting Foxp3 expression. Importantly, purified CD4+CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1β. Further analyses showed that the ability of IL-1β to maintain Foxp3 expression in CD25+ T cells was dependent on TGF-β1 and IL-2 expression in Foxp3+Tregs and CD25− effectors T cells respectively. Exposure of CD4+CD25+ T cells to IL-1β enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1β can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity

Transcriptome analysis on individuals suffering from treatment-resistant depression with the use of machine learning techniques

Pomimo licznych badań na temat depresji przeprowadzonych na przestrzeni ostatnich dziesięcioleci, jej etiologia w dalszym ciągu nie jest poznana. Biorąc pod uwagę dużą liczbę obecnych w literaturze teorii rozwinięcia tej choroby, mnogość różnych markerów biologicznych z nią powiązanych, jak i odsetek pacjentów niereagujących w spodziewany sposób na dostępne terapie farmakologiczne, można wnioskować, że termin „depresja” obejmuje tak naprawdę kilka kategorii chorobowych o pokrywającym się spektrum objawów. Takie rozumienie depresji pozwala na zauważenie konieczności wprowadzenia dobierania metod terapeutycznych w sposób spersonalizowany.Wykorzystując dane o odpowiednich biomarkerach wpołączeniu z informacjami na temat rokowania pacjentów i reakcji na różne środki farmakologiczne, możliwe stanie się rozwinięcie modeli uczenia maszynowego zdolnych do dopasowania terapii dla każdego chorego w sposób indywidualny. Aby jednak było to możliwe, należy zebrać odpowiednio duży zbiór danych wysokiej jakości, co staje się realne dzięki nowoczesnym technikom sekwencjonowania genów.W bieżącej pracy dokonano analizy transkryptomów osób chorych na depresję lekooporną w porównaniu do osób zdrowych, jak i po podaniu ketaminy, co pozwoliło na określenie genów o zmienionym poziomie ekspresji wopisanych warunkach. Uzyskane informacje zostały użyte do analizy ontologicznej, jak i wykrycia SNPs przy pomocy wytrenowanego modelu uczenia głębokiego. Otrzymane wyniki sugerują aktywację szlaku sygnalizacji interferonów w grupie z TRD, jak i nadmierną ekspresję oraz zmienność w obrębie genów kodujących białka związane z strukturą i funkcjonowaniem erytrocytów w grupie osób odpowiadających na terapię ketaminą.Despite it being a topic of numerous studies over the past decades, the etiology of depression remains unknown. Taking into account a large number of theories of the development of this disease present in the literature, the multitude of various biological markers associated with it, as well as the percentage of patients not responding in the expected manner to the available pharmacological therapies, it can be concluded that the term "depression" actually covers several disease categories with an overlapping set of symptoms. Such an understanding of depression allows us to notice the need to select therapeutic methods in a personalized manner.By using data on relevant biomarkers in conjunction with information on patient prognosis and response to various pharmacological agents, it will be possible to develop machine learning models capable of tailoring treatments for each patient individually. However, a sufficiently large set of high-quality data must be collected in order to accomplish this scenario, which is being made possible by modern gene sequencing techniques.In the present study, the transcriptomes of people suffering from treatment-resistant depression were analyzed in comparison to healthy controls as well as before and after ketamine administration. This allowed for the determination of genes with altered expression levels under the described conditions. The information obtained was used for ontological analysis as well as for the detection of SNPs using a pre-trained deep learning model. The obtained results indicate the activation of the interferon signaling pathway in the TRD group, as well as over-expression and variability within the genes encoding proteins related to the structure and functioning of erythrocytes in the group of responders to ketamine therapy

mGlu receptors as a target for potential antidepressants

Depresja, chociaż jej objawy są często bagatelizowane, stanowi jedną z najczęstszych przyczyn upośledzenia na świecie, uniemożliwiając cierpiącym na nią normalne funkcjonowanie w społeczeństwie. Dostępne na rynku terapie farmakologiczne bazują  w większości na teorii monoaminergicznej, tymczasem okazuje się, że to nie deficyty w stężeniu monoamin, a zaburzenia w poziomie glutaminianu mogą stać za patofizjologią tej choroby. Glutaminian, główny pobudzający neuroprzekaźnik w ośrodkowym układzie nerwowym, pełni istotną rolę w wielu aspektach funkcjonowania człowieka, w tym w powstawaniu stanów emocjonalnych. Wiąże się on z dwoma typami receptorów: jonotropowymi i metabotropowymi i, okazuje się, że to właśnie związki, działające na te drugie mają potencjał stania się nowoczesnymi skutecznymi i, przede wszystkim, bezpiecznymi, lekami przeciwdepresyjnymi.Depression is one of the most common causes of disability worldwide and yet the impact it has on patients’ lives is still being underestimated. Most of the therapeutic agents act on the monoamine system which is consistant with the monoamine hypothesis of depression. However, it turns out that the monoamine defficiency is not actually responsible for developing the symptoms of depression. It is, in, fact, the glutamatergic neutrotransmission that is linked to the patophysiology of this disease. Glutamate, as the main excitory neurotransmitter of the central nervous system, plays an important role in mediating cognitive-emotional behaviours. There are two types of glutamatergic receptors present in the brain: ionotropic and metabotropic ones and it turns out that the latter may be a target for developing modern, effective and safe antidepressants