Immune-mediated Attack Research Articles

Immunotherapy for Type 1 Diabetes: Mechanistic Insights and Impact of Delivery Systems.

Type 1 Diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, leading to hyperglycemia and various complications. Despite insulin replacement therapy, there is a need for therapies targeting the underlying autoimmune response. This review aims to explore the mechanistic insights into T1D pathogenesis and the impact of delivery systems on immunotherapy. Genetic predisposition and environmental factors contribute to T1D development, triggering an immune-mediated attack on β-cells. T cells, particularly CD4+ and CD8+ T cells, play a central role in β-cell destruction. Antigen- specific immunotherapy is a unique way to modify the immune system by targeting specific antigens (substances that trigger the immune system) for immunotherapy. It aims to restore immune tolerance by targeting autoantigens associated with T1D. Nanoparticle-based delivery systems offer precise antigen delivery, promoting immune tolerance induction. Various studies have demonstrated the efficacy of nanoparticle-mediated delivery of autoantigens and immunomodulatory agents in preclinical models, and several patents have been made in T1D. Combining antigen-specific immunotherapy with β-cell regeneration strategies presents a promising approach for T1D treatment. However, challenges remain in optimizing delivery systems for targeted immune modulation while ensuring safety and efficacy.

Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via β2 Adrenergic Receptor Signaling.

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune-mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)-KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL-KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)-dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep-deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

A Review on Autoimmune Diseases: Recent Advances and Future Perspectives

Autoimmune diseases represent a diverse group of disorders characterized by immune-mediated attacks on the body’s own tissues and organs. This review provides a comprehensive overview of autoimmune diseases, covering their definition, classification, epidemiology, etiology, pathogenesis, clinical manifestations, current treatments, and future research directions. Autoimmune diseases can be categorized into organ-specific (e.g., type 1 diabetes, Hashimoto's thyroiditis) and systemic (e.g., systemic lupus erythematosus, rheumatoid arthritis) conditions, each with distinct clinical presentations and underlying mechanisms. Genetic predisposition, environmental triggers, and immunological dysregulation play critical roles in disease development. Common symptoms include fatigue, joint pain, skin manifestations, and organ-specific dysfunction, contributing to significant morbidity and impaired quality of life. Current treatment strategies encompass immunosuppressive therapies, disease-modifying drugs, and emerging biologic agents targeting specific immune pathways. Advances in genomics, immunology, and precision medicine offer promising avenues for personalized diagnosis and treatment optimization. Future research directions include further elucidating disease heterogeneity, identifying novel biomarkers, and developing targeted immunotherapies to achieve long-term remission and improve patient outcomes. Understanding the complex interplay of genetic, environmental, and immunological factors is crucial for advancing therapeutic approaches and mitigating the global burden of autoimmune diseases. Enhanced collaboration across disciplines and continued investment in research are essential to translate these insights into clinical practice and benefit patients worldwide.

The Impact of Cytomegalovirus Infection on Natural Killer and CD8+ T Cell Phenotype in Multiple Sclerosis.

Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.

NK-клетки, предобработанные эстриолом и клетками комменсальной флоры, регулируют созревание Treg и Th17 из CD4+ лимфоцитов у больных рассеянным склерозом и здоровых доноров

Multiple sclerosis (MS) is an inflammatory chronic disease of the central nervous system, one of the pathogenetic mechanisms of which is an immune-mediated attack to the myelin sheath of nerve axons under the control of autoreactive T cells. NK cells, one of subtypes of ILC cells, have the ability to regulate autoimmune mechanisms through the production of cytokines or cytotoxic effects directly against effector cells, such as autoreactive T cells or antigen-presenting cells. At the same time, they can also lyse microglial, astrocyte, and oligodendrocyte cells, indicating a dual function of NK cells in MS. The influence of the pregnancy hormone estriol (E3) and commensal microflora on the ability of NK cells to modulate the level of T regulatory (Treg) and IL-17-producing (Th17) lymphocytes from patients with multiple sclerosis (MS) in comparison with healthy donors was studied. To activate NK cells, Ecsherichia coli K12 and Lactobacillus plantarum 8R-A3 strains were used. The phenotype of Treg and Th17 cells was assessed by flow cytometry using monoclonal antibody staining. It was found that NK cells incubated with E3 and E. coli stimulate the formation of Tregs, and pretreatment of NK cells with L. plantarum inhibits the formation of Th17 from CD4+ lymphocytes. In general, regulatory lymphocytes from MS patients turned out to be more sensitive to the influence of NK cells than cells from healthy donors.

Oncolytic virotherapy in cancer treatment: challenges and optimization prospects.

Oncolytic viruses (OVs) are emerging cancer therapeutics that offer a multifaceted therapeutic platform for the benefits of replicating and lysing tumor cells, being engineered to express transgenes, modulating the tumor microenvironment (TME), and having a tolerable safety profile that does not overlap with other cancer therapeutics. The mechanism of OVs combined with other antitumor agents is based on immune-mediated attack resistance and might benefit patients who fail to achieve durable responses after immune checkpoint inhibitor (ICI) treatment. In this Review, we summarize data on the OV mechanism and limitations of monotherapy, which are currently in the process of combination partner development, especially with ICIs. We discuss some of the hurdles that have limited the preclinical and clinical development ofOVs. We also describe the available data and provide guidance for optimizing OVs in clinical practice, as well as a summary of approved and promising novel OVs with clinical indications.

Uncovering the Genetics and Physiology behind Optic Neuritis.

Optic neuritis (ON) is an inflammatory condition affecting the optic nerve, leading to vision impairment and potential vision loss. This manuscript aims to provide a comprehensive review of the current understanding of ON, including its definition, epidemiology, physiology, genetics, molecular pathways, therapy, ongoing clinical studies, and future perspectives. ON is characterized by inflammation of the optic nerve, often resulting from an autoimmune response. Epidemiological studies have shown a higher incidence in females and an association with certain genetic factors. The physiology of ON involves an immune-mediated attack on the myelin sheath surrounding the optic nerve, leading to demyelination and subsequent impairment of nerve signal transmission. This inflammatory process involves various molecular pathways, including the activation of immune cells and the release of pro-inflammatory cytokines. Genetic factors play a significant role in the susceptibility to ON. Several genes involved in immune regulation and myelin maintenance have been implicated in the disease pathogenesis. Understanding the genetic basis can provide insights into disease mechanisms and potential therapeutic targets. Therapy for ON focuses on reducing inflammation and promoting nerve regeneration. Future perspectives involve personalized medicine approaches based on genetic profiling, regenerative therapies to repair damaged myelin, and the development of neuroprotective strategies. Advancements in understanding molecular pathways, genetics, and diagnostic tools offer new opportunities for targeted therapies and improved patient outcomes in the future.

Nodopathy: clinic, diagnosis, treatment. Clinical description

AIM: Evaluation of the significance and possibilities of laboratory-instrumental diagnostic methods in establishing the diagnosis and selection of targeted therapy in patients with nodopathies.
 MATERIALS AND METHODS: System analysis of data from foreign and domestic literature with the presentation of a clinical case.
 RESULTS: Polyneuropathies are classified as demyelinating or axonal based on electrophysiological studies. However, in 2015, in addition to axonal and demyelinating neuropathies, it was proposed to distinguish a separate pathophysiological group — nodopathies. The pathogenesis of nodopathies may differ depending on the type of ion channels involved in the process, but always leads to a loss of excitability of the axon membrane; in the nodal region the membrane becomes inexcitable. Such neuropathies are characterized by transient conduction blocks followed by the development of axonal degeneration. Typical examples of nodopathies are acute motor axonal neuropathy, as well as multifocal motor neuropathy. Current pathophysiological understanding of specialized nodal regions (nodes of Ranvier) and associated axoglial proteins is growing. Hypotheses have been put forward about their role in the pathogenesis of immune-mediated attack on the peripheral myelinated axon. Recently, high titers of antibodies directed against a number of key adhesion molecules have been identified in both acute and chronic inflammatory neuropathies. These facts add to the differences in differential diagnosis between axonal and demyelinating peripheral neuropathies. New disease classification schemes based on seropositivity, improved electrophysiological and ultrasound classification, and identification of putative underlying pathological targets and mechanisms are being rapidly developed.
 CONCLUSION: Using our clinical example, we demonstrated the capabilities of laboratory and instrumental diagnostic methods in establishing a diagnosis in a patient with one of the forms of nodopathies — multifocal motor neuropathy.

Clonal Hematopoiesis in Patients with Immune Thrombocytopenia: Preliminary Results of a Cross-Sectional Study

Immune thrombocytopenia (ITP) is an acquired disorder marked by immune-mediated attack to platelets. However, the borders between ITP and clonal cytopenias, such as low risk myelodysplastic syndromes, may be difficult to establish. Detection of somatic mutations on peripheral blood leukocytes (PBL) through next generation sequencing (NGS) is gaining diagnostic and prognostic power in myeloid disorders and may be found also in individuals without blood malignancies, namely clonal hematopoiesis with indeterminate potential (CHIP). The prevalence and significance of CHIP in immune-mediated hematological diseases, such as ITP, is not clearly known. Here we present the preliminary results of a cross-sectional study on adult ITP patients followed at our clinics from 2019 until March 2023. History of any hematological malignancy was an exclusion criterion. An NGS study on PBL was performed by Ion Torrents5, Ion Reporters software 5.2, evaluating mutations in 69 potentially oncogenic genes present in the Oncomine Myeloid Research Assay diagnostic panel. Only mutations with a variant allele frequency (VAF) of 2% were considered, while mutations with VAF > 40% were regarded as potentially germline and discarded. To correlate mutational status with clinical features, a two-tailed Fisher's exact test was used for analysis of dichotomic variables, while a two-sided student's t was used for continuous ones. We included 37 ITP patients (Table 1), 14 of which (38%) had at least one mutation. After exclusion of 4 mutations with VAF > 40%, a total of 17 mutations were considered, affecting 11/37 (30%) patients (NGS-positive). Mutated genes were TET2 (7/17, 41%), DNMT3A (4/17, 18%), SRSF2 (2/17, 12%), and SF3B1, MPL, ASXL1 and NF1 in 1/17 (6%) case each. All patients, except two, had received at least one treatment line (steroids +/- intravenous immunoglobulins), 32 (86%) and 14 (38%) subjects 2 or 3 lines, respectively. Median age of NGS-positive was significantly higher than NGS-negative patients: 73 years, interquartile range (IQR) 68 - 76 vs 62 years, IQR 52 - 70 (p = 0.02). NGS-positive had a slightly lower rate of complete response (CR; PLT > 100 x 10 9/L) after steroid treatment, compared with NGS-negative patients (40% vs 60%, respectively). Among the 9 NGS-positive patients who received thrombopoietin receptor agonists (TPO-RA), only 2 were evaluated before, and the remaining after a median of 2.6 years from TPO-RA start. Considering the 9 patients treated with TPO-RA, NGS-positive had a slightly lower rate of CR than NGS-negative patients (44% vs 79%, respectively). In this respect, we did not find substantial disparities in distribution or VAF of gene mutations between patients who fully responded to TPO-RA and those failing to achieve CR. With the caveat of a cross-sectional analysis in a limited number of cases, these data show the presence of CHIP in 1/3 of multi-treated ITP patients, a frequency similar to that of a much more elderly Italian population >80-year-old (Rossi et al, Blood. 2021), suggesting a possible role of autoimmunity/inflammation and treatment in clonal selection.

Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance.

Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and immunological responses. The role of H4R in neurons of the CNS has recently been revealed. However, the precise role of H4R in neuronal function remains inadequately understood. The objective of this work was to investigate the impact of JNJ 10191584 (JNJ), a highly effective and specific H4R antagonist, on the development of experimental autoimmune encephalomyelitis (EAE) and to gain insight into the underlying mechanism involved. In this study, we examined the potential impact of JNJ therapy on the course of EAE in SJL/J mice. EAE mice were administered an oral dose of JNJ at a concentration of 6 mg/kg once a day, starting from day 10 and continuing until day 42. Afterward, the mice's clinical scores were assessed. In this study, we conducted additional research to examine the impact of JNJ on several types of immune cells, specifically Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγt), and regulatory T (Tregs; Foxp3 and TGF-β1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγt, Foxp3, and TGF-β1 in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4+IFN-γ+, CD4+T-bet+, CD4+IL-9+, CD4+IRF4+, CD4+IL-17A+, and CD4+RORγt+ cells were shown to decrease, whereas the percentages of CD4+TGF-β1+ and CD4+Foxp3+ cells were observed to increase in EAE mice treated with JNJ. Therefore, the HR4 antagonist positively affected the course of EAE by modulating the signaling of transcription factors. The identified results include possible ramifications in the context of MS treatment.

The Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Preventing the Destruction of CD34+ Haematopoietic Stem Cells in Aplastic Anaemia by Modulating the Th1/Th2 Balance.

Aplastic anaemia (AA) is a haematopoietic disorder caused by immune-mediated attack on haematopoietic stem cells (HSCs). Stem cell transplantation and immunosuppressive therapy remain the major treatment choice for AA patients but have limited benefits and undesired side effects. The aim of our study was to clarify the protective role of immunity of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in AA. Our integrative analysis demonstrated that CIHH pre-treatment significantly improved haematopoiesis and survival in an AA rat model. We further confirmed that CIHH pre-treatment was closely associated with the Th1/Th2 balance and a large number of negative regulatory haematopoietic factors, such as TNF-α and IFN-γ, produced by hyperactive Th1 lymphocytes released in AA rats, which induced the death program in a large number of CD34+ HSCs by activating the Fas/FasL apoptosis pathway, while CIHH pre-treatment effectively downregulated the expression of TNF-α and IFN-γ, resulting in a reduction in Fas antigen expression in CD34+ HSCs. In summary, this study provides evidence that CIHH has good protective effect against AA by modulating immune balance in Th1/Th2 cells and may provide a new therapeutic strategy.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination.

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.

A Case Report of Association between Canine Hypothyroidism and Diabetes

Hypothyroidism is the most common hormonal disorder in dogs because of the low production of the hormones thyroxine (T4) and triiodothyronine (T3) by the thyroid gland. The main cause of hypothyroidism in adult dogs is primary hypothyroidism associated with destruction of the thyroid gland in lymphocytic or autoimmune thyroiditis, followed by idiopathic thyroid degeneration or idiopathic follicular atrophy. Dogs affected by hypothyroidism may develop diabetes mellitus due to the propensity for the development of other endocrine diseases associated with the immune-mediated attack against cellular antigens associated with endocrine system. In this case report, an eleven-year-old male Lhasa Apso was presented to the clinical facility with signs of apathy, anorexia and non-pruritic bilateral symmetric alopecia that extended to the tip of the tail but sparing the head and limbs. Other clinical manifestations included polyuria, polydipsia, and bilateral cataracts. The animal was submitted to the blood count, T4, T3, TSH dosage, biochemical tests, and imaging tests (cervical and abdominal ultrasonography). Exam results demonstrate the presence of hypothyroidism and diabetes mellitus. Since hypothyroidism corresponds to the most common endocrine disorder in dogs, and they are prone to the development of diabetes mellitus, the veterinarian must be aware of the clinical manifestations of these diseases.

Liraglutide protects β-cells in novel human islet spheroid models of type 1 diabetes

To enable accurate, high-throughput and longer-term studies of the immunopathogenesis of type 1 diabetes (T1D), we established three in-vitro islet-immune injury models by culturing spheroids derived from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. In all models, β-cell function declined as manifested by increased basal and decreased glucose-stimulated insulin release (GSIS), and decreased intracellular insulin content. Additional hallmarks of T1D progression such as loss of the first-phase insulin response (FFIR), increased proinsulin-to-insulin ratios, HLA-class I expression, and inflammatory cytokine release were also observed. Using these models, we show that liraglutide, a glucagon-like peptide 1 receptor agonist, prevented loss of GSIS under T1D-relevant stress, by preserving the FFIR and decreasing immune cell infiltration and cytokine secretion. Our results corroborate that liraglutide mediates an anti-inflammatory effect that aids in protecting β-cells from the immune-mediated attack that leads to T1D.

Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a major cause of morbidity and mortality following HSCT. Regulatory CD4+ T cells (Tregs) are a rare cell type crucial for immune system homeostasis, limiting the activation and differentiation of effector T cells (Teff) that are self-reactive or stimulated by foreign antigen exposure. Adoptive cell therapy (ACT) with Treg has demonstrated, first in murine models and now in patients, that prophylactic Treg infusion can also suppress GVHD. While clinical trials have demonstrated Treg reduce severe GVHD occurrence, several impediments remain, including Treg variability and practical need for individualized Treg production for each patient. Additionally, there are challenges in the use of in vitro expansion techniques and in achieving in vivo Treg persistence in context of both immune suppressive drugs and in lymphoreplete patients being treated for GVHD. This review will focus on 3 main translational approaches taken to improve the efficacy of tTreg ACT in GVHD prophylaxis and development of treatment options, following HSCT: genetic modification, manipulating TCR and cytokine signaling, and Treg production protocols. In vitro expansion for Treg ACT presents a multitude of approaches for gene modification to improve efficacy, including: antigen specificity, tissue targeting, deletion of negative regulators/exhaustion markers, resistance to immunosuppressive drugs common in GVHD treatment. Such expansion is particularly important in patients without significant lymphopenia that can drive Treg expansion, enabling a favorable Treg:Teff ratio in vivo. Several potential therapeutics have also been identified that enhance tTreg stability or persistence/expansion following ACT that target specific pathways, including: DNA/histone methylation status, TCR/co-stimulation signaling, and IL-2/STAT5 signaling. Finally, this review will discuss improvements in Treg production related to tissue source, Treg subsets, therapeutic approaches to increase Treg suppression and stability during tTreg expansion, and potential for storing large numbers of Treg from a single production run to be used as an off-the-shelf infusion product capable of treating multiple recipients.

Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q.

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.

Old is new again: Emergence of thromboembolic complications in cancer patients on immunotherapy

Cancer immunotherapy has emerged as one of the most important new treatments for cancer in many years, moving rapidly to front-line therapy for several cancers. Cancer immunotherapy is based on treatment with immune checkpoint inhibitors (ICI), which are monoclonal antibodies directed toward immunoregulatory proteins including PD-1, PD-L1 and CTLA-4. ICI inhibit interactions between these proteins and their ligands, disabling physiologic immune regulatory networks and enhancing anti-tumor immunity. However, since the immune response cannot be directed specifically to the tumor, ICI are associated with immune-related adverse events (irAEs) resulting from immune-mediated attack of normal tissues. We and others have reported a high incidence of thrombosis in patients treated with ICI, which may approach 20%. Given the rapidly increasing use of ICIs, it is clear that ICI-Associated Thrombosis (IAT) is a major emerging clinical problem. However, there is a remarkable knowledge gap concerning mechanisms of IAT. IAT may be a composite irAE resulting from activation of blood and vascular cells, leading to thromboinflammation. Cancer itself is an inflammatory disorder, and inducing further inflammation through ICI administration may stimulate procoagulant activity by multiple cell types. Moreover, some blood and vascular cells express ICI target proteins. Here, we review the results of several studies describing the clinical manifestations of IAT, as well as our recent studies demonstrating that elevated levels of myeloid derived suppressor cells and inflammatory cytokines may serve as biomarkers of IAT. It is hoped that the concepts reviewed here may stimulate further research into this important clinical problem.

Translocator Protein Ligand PIGA1138 Reduces Disease Symptoms and Severity in Experimental Autoimmune Encephalomyelitis Model of Primary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system (CNS) caused by CNS infiltration of peripheral immune cells, immune-mediated attack of the myelin sheath, neuroinflammation, and/or axonal/neuronal dysfunctions. Some drugs are available to cope with relapsing-remitting MS (RRMS) but there is no therapy for the primary progressive MS (PPMS). Because growing evidence supports a regulatory role of the translocator protein (TSPO) in neuroinflammatory, demyelinating, and neurodegenerative processes, we investigated the therapeutic potential of phenylindolyilglyoxylamydes (PIGAs) TSPO ligands in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice mimicking the human PPMS. MOG-EAE C57Bl/6-mice were treated by TSPO ligands PIGA839, PIGA1138, or the vehicle. Several methods were combined to evaluate PIGAs-TSPO ligand effects on MOG-EAE symptoms, CNS infiltration by immune cells, demyelination, and axonal damages. PIGA1138 (15mg/kg) drastically reduced MOG-EAE mice clinical scores, ameliorated motor dysfunctions assessed with the Catwalk device, and counteracted MOG-EAE-induced demyelination by preserving Myelin basic protein (MBP) expression in the CNS. Furthermore, PIGA1138-treatment prevented EAE-evoked decreased neurofilament-200 expression in spinal and cerebellar axons. Moreover, PIGA1138 inhibited peripheral immune-CD45 + cell infiltration in the CNS, suggesting that it may control inflammatory mechanisms involved in PPMS. Concordantly, PIGA1138 enhanced anti-inflammatory interleukin-10 serum level in MOG-EAE mice. PIGA1138-treatment, which increased neurosteroid allopregnanolone production, ameliorated all pathological biomarkers, while PIGA839, unable to activate neurosteroidogenesis in vivo, exerted only moderate/partial effects in MOG-EAE mice. Altogether, our results suggest that PIGA1138-based treatment may represent an interesting possibility to be explored for the innovation of effective therapies against PPMS.

Modeling acute graft-versus-host disease (aGVHD) in murine bone marrow transplantation (BMT) models with MHC disparity.

For more than 50years, hematopoietic stem cell transplantation (HSCT) has been the major curative therapy for hematological malignancies and genetic disorders, but its success is limited by the development of graft-versus-host disease (GVHD). GVHD represents a post-transplantation disorder representing the immune-mediated attack of transplant-derived T cells against recipient tissue finally leading to increased morbidity and mortality of the recipient. GVHD develops if donor and recipient are disparate in major or minor histocompatibility antigens (MHC, miHA). Most of the initial knowledge about the biology of GVHD is derived from murine bone marrow transplantation (BMT) models. Of course, GVHD mouse models do not reflect one to one the human situation, but they contribute significantly to our understanding how conditioning and danger signals activate the immune system, enlighten the role of individual molecules, e.g., cytokines, chemokines, death-inducing ligands, define the function of lymphocytes subpopulations for GVHD development and have significant impact on establishing new treatment and prevention strategies used in clinical HSCT. This chapter describes in detail the procedure of allogeneic BMT and the development of GVHD in two commonly used allogeneic murine BMT models (B6→B6.bm1, B6→B6D2F1) with different MHC disparities, which can be used as a basis for advanced studies of GVHD pathology or the development of new treatment strategies.