Immunomodulatory Interventions Research Articles

Single-Cell RNA and TCR Sequencing Reveals Novel Immune Cell Networks in Poorly Controlled Epilepsy (S35.001)

<h3>Objective:</h3> To perform a deep dissection of the role and regulation of innate and adaptive immunity in poorly controlled (PC) and well controlled (WC) focal epilepsy. <h3>Background:</h3> The role of the immune system in the pathophysiology of epilepsy has been underappreciated. There is mounting evidence that surgical epilepsy samples contain infiltrating immune cells. However, their phenotype and the mechanism of their recruitment are not well understood. <h3>Design/Methods:</h3> Individuals with focal epilepsy were prospectively recruited from Brigham and Women’s Hospital outpatient epilepsy clinics. Epilepsy subjects were divided into a WC or PC group based on whether they had seizures within the 6 months prior to study enrollment. Age-and sex-matched healthy controls were also included. Using peripheral blood mononuclear cells (PBMCs), we performed a detailed analysis of ~84,000 PBMCs using single-cell RNA and T-cell receptor sequencing (scRNA/TCR-seq). <h3>Results:</h3> A total of 107 subjects were recruited including 87 epilepsy subjects and 20 healthy controls. 49.5% of epilepsy subjects had a seizure within 6 months of recruitment, and 52% had an MRI abnormality. scRNA/TCR-seq data highlighted differences in the composition of adaptive and innate immune cells in well-controlled and poorly-controlled subjects. In particular, memory CD4+ and CD8+ T-cells as well as NK T-cells that express cytotoxic cytokines such as granzyme and perforin, constitute a higher proportion of T-cells in PC epilepsy subjects, whereas CD14+ and CD16+ monocytes, and B memory cells show depletion. Moreover, ligand/receptor network analyses using the CellChat computational tool identified several statistically significant intercellular interactions such as the Selectin cell adhesion pathway that is involved in the recruitment of leukocytes to the site of injury in the brain. <h3>Conclusions:</h3> We identified disrupted adaptive and innate immune homeostasis in poorly controlled focal epilepsy. Network analyses revealed ligand/receptor pairs with well-known roles in lymphocyte trafficking that may be targeted for immunomodulatory interventions to treat epilepsy. <b>Disclosure:</b> Dr. Sarkis has nothing to disclose. Ms. Amer has nothing to disclose. Mr. Mares has nothing to disclose. Mr. Hobson has nothing to disclose. The institution of Vilas Menon has received research support from Chan Zuckerberg Initiative. The institution of Vilas Menon has received research support from National Institute of Aging. Vilas Menon has received personal compensation in the range of $0-$499 for serving as a Grant Reviewer with National Institutes of Health. Dr. Pennell has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for American Epilepsy Society. The institution of Dr. Pennell has received research support from NIH. The institution of an immediate family member of Dr. Pennell has received research support from Department of Defense. The institution of an immediate family member of Dr. Pennell has received research support from Environmental Protection Agency. The institution of an immediate family member of Dr. Pennell has received research support from NIH. The institution of an immediate family member of Dr. Pennell has received research support from Advanced Energy Consortium. Dr. Pennell has received publishing royalties from a publication relating to health care. Dr. Elyaman has nothing to disclose.

Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.

To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = -0.054, p = 0.880). There were no statistically significant correlations between manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan (-0.72 (-2.9 to 1.6) mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake. Manganese-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.

Immunometabolic depression: from conceptualization towards implementation

AbstractThe burden on society by depression is undisputable, partly due to a chronic course pattern and depression’s large heterogeneity that contributes to non-response to standard treatments. Using data from the Netherlands Study of Depression and Anxiety (NESDA, www.nesda.nl), Penninx will illustrate both points. When examining the course of depression, especially when also considering the transitions into other affective disorders over time, chronicity is clearly more the rule than the exception (Verduijn et al. BMC Med 2017). Considering depression’s heterogeneity could lead to precision psychiatry approaches that help reduce depression’s chronicity. Immuno-metabolic dysregulations seem to vary as a function of depression heterogeneity: dysregulations map more consistently to “atypical” neurovegetative symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis). Findings are confirmed when utilizing genome-wide gene expression as well as DNA information (Milaneschi et al. Biol Psychiatry 2020). Preliminary treatment studies suggest that the presence of immuno-metabolic dysregulations in depression moderates antidepressant effects of standard or novel (immunomodulatory) interventions. An immuno-metabolic depression dimension could dissect depression’s heterogeneity and potentially match depressed subgroups to treatments with higher likelihood of clinical success.Disclosure of InterestNone Declared

Neuropsychiatric Testing Provides Objective Insight Into Beneficial Effects Of Intravenous Immunoglobulins In Patients With Pediatric Acute-Onset Neuropsychiatric Syndrome

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is defined by acute beginning of diverse neuropsychiatric symptoms, likely in the setting of underlying immune dysfunction. Thus, immunomodulatory interventions have a crucial therapeutic role, but objective post-treatment evaluations remain challenging given disease complexity. We used standardized neuropsychiatric testing to assess how intravenous immunoglobulins (IVIG) impact cognitive function.

Immune-related adverse events in checkpoint blockade: Observations from human tissue and therapeutic considerations.

Checkpoint inhibitors (CPIs) are monoclonal antibodies which, by disrupting interactions of immune checkpoint molecules with their ligands, block regulatory immune signals otherwise exploited by cancers. Despite revolutionary clinical benefits, CPI use is associated with an array of immune-related adverse events (irAEs) that mirror spontaneous autoreactivity. Severe irAEs necessitate pausing or stopping of CPI therapy and use of corticosteroids and/or other immunomodulatory interventions. Despite increasingly widespread CPI use, irAE pathobiology remains poorly understood; its elucidation may point to targeted mitigation strategies and uncover predictive biomarkers for irAE onset in patients, whilst casting new light on mechanisms of spontaneous immune-mediated disease. This review focuses on common CPI-induced irAEs of the gut, skin and synovial joints, and how these compare to immune-mediated diseases such as ulcerative colitis, vitiligo and inflammatory arthritis. We review current understanding of the immunological changes reported following CPI therapy at the level of peripheral blood and tissue. Many studies highlight dysregulation of cytokines in irAE-affected tissue, particularly IFNγ and TNF. IrAE-affected tissues are also predominantly infiltrated by T-cells, with low B-cell infiltration. Whilst there is variability between studies, patients treated with anti-programmed cell death-1 (PD-1)/PDL-1 therapies seem to exhibit CD8+ T-cell dominance, with CD4+ T-cells dominating in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy. Interestingly, CD8+CXCR3+ T-cells have been reported to be elevated in gastrointestinal, dermatological and musculoskeletal -irAE affected tissues. These findings may highlight potential opportunities for therapeutic development or re-deployment of existing therapies to prevent and/or improve the outcome of irAEs.

Antiviral Approaches against Influenza Virus.

Preventing and controlling influenza virus infection remains a global public health challenge, as it causes seasonal epidemics to unexpected pandemics. These infections are responsible for high morbidity, mortality, and substantial economic impact. Vaccines are the prophylaxis mainstay in the fight against influenza. However, vaccination fails to confer complete protection due to inadequate vaccination coverages, vaccine shortages, and mismatches with circulating strains. Antivirals represent an important prophylactic and therapeutic measure to reduce influenza-associated morbidity and mortality, particularly in high-risk populations. Here, we review current FDA-approved influenza antivirals with their mechanisms of action, and different viral- and host-directed influenza antiviral approaches, including immunomodulatory interventions in clinical development. Furthermore, we also illustrate the potential utility of machine learning in developing next-generation antivirals against influenza.

Abstract P045: γδ T cells contribute to an inflammatory and immunosuppressive microenvironment in lung squamous cell carcinoma tumorigenesis

Abstract Lung cancer (LC) is the leading cause of cancer death worldwide. Lung squamous cell carcinoma (LSCC) is the second most prevalent subtype of LC, accounting for approximately 22% of cases. It is strongly associated with smoking, with approximately 90% of cases attributable to cigarette smoke exposure. Despite the strong association with smoking, not all smokers will develop lung cancer. From this, two key questions arise: which patients will develop the lesions preceding LSCC, and among those, which will progress to frank carcinoma? Stratification of at-risk patients for diversion into intervention and prevention strategies, such as increased monitoring and chemical interception, remains an urgent need, and a greater understanding of the factors contributing to progression of LSCC premalignancy is critical in addressing this. Previous evidence suggests a role for the immune system in the development of preinvasive disease, and we hypothesize that immune differences between at-risk smokers may also play a role in which patients progress on to frank LSCC and which do not. Using the N-Nitrosotris-(2-chloroethyl) urea (NTCU) carcinogen-induced murine model of LSCC, we sought to explore the immune contexture of LSCC premalignancy in both NTCU-sensitive and NTCU-resistant mouse strains. We immunophenotyped mouse lungs via flow cytometry and imaging mass cytometry over the course of disease initiation and progression to carcinoma. We found that although the frequency of γδ T cells in control animals were the same between sensitive and resistant mice, in sensitive mice the frequency of γδ T cells and the expression of activation/exhaustion markers increased with histological progression of PMLs, along with a decrease in the frequency of cytotoxic CD8+ T cells. Given that pro-tumor γδ T cells have been established to mediate airway inflammation via recruitment of myeloid cells (e.g., macrophages, neutrophils, and myeloid derived suppressor cells) and to influence maturation/exhaustion of T cells, these findings suggest γδ T cells potentially contribute to the early establishment of an inflammatory and immunosuppressive microenvironment in developing LSCC premalignancy. By better understanding how immune alterations within the precancerous microenvironment contribute to lesion progression, immunomodulatory intervention agents can be developed and deployed in at-risk patients to ameliorate the development of frank lung squamous cell carcinoma and ultimately reduce LC mortality. Citation Format: Táchira Pichardo, Anna Belkina, Jennifer Snyder-Cappione, Jennifer Beane, Sarah Mazzilli. γδ T cells contribute to an inflammatory and immunosuppressive microenvironment in lung squamous cell carcinoma tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P045.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

CD4+IL9+ (Th9) cells as the major source of IL-9, potentially modulate Th17/Treg mediated host immune response during experimental cerebral malaria

Th9, a new subgroup of CD4+T cells is characterized by its specific cytokine IL-9, is a critical factor in allergic diseases, cancers and parasitic infections. This study aimed to explore the potential roles of Th9 cells in the immunopathogenesis of ECM. In splenocytes sourced from uninfected, PbA and Py infected mice, Th9 cells were characterised by flow cytometry, cell sorting and qPCR. Enhancement of CD4+IL-9+ (Th9) cells were observed in both the infections, which corroborated with increased expression of the differentiating transcription factors. Moreover, crucial cytokine receptors (IL-4R, TGF-βR, IL-6R) as well as chemokine receptors (CCR3, CCR6 and CCR7) and activation marker (CD96), demonstrated elevation upon PbA infection in splenic Th9 cells. Furthermore, Neutralization of IL-9 along with IL-6 enhanced host survivability, reduced mean neurological score of ECM. However, anti- IL-9 treatment also down regulated frequency of Th17 cells, and its transcription factors pSTAT3, RORγT along with depleted Il-1β and Il-6 expression. In sum, understanding how IL-9 producing CD4+ T-cells can alter Th17/Treg ratio and by that modulate host’s immune response, could pave the way for developing immunomodulatory interventions against cerebral malaria.

Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening.

Pulmonary hypertension (PH) is a progressive disease that arises from multiple etiologies and ultimately leads to right heart failure as the predominant cause of morbidity and mortality. In patients, distinct inflammatory responses are a prominent feature in different types of PH, and various immunomodulatory interventions have been shown to modulate disease development and progression in animal models. Specifically, PH-associated inflammation comprises infiltration of both innate and adaptive immune cells into the vascular wall of the pulmonary vasculature—specifically in pulmonary vascular lesions—as well as increased levels of cytokines and chemokines in circulating blood and in the perivascular tissue of pulmonary arteries (PAs). Previous studies suggest that altered hemodynamic forces cause lung endothelial dysfunction and, in turn, adherence of immune cells and release of inflammatory mediators, while the resulting perivascular inflammation, in turn, promotes vascular remodeling and the progression of PH. As such, a vicious cycle of endothelial activation, inflammation, and vascular remodeling may develop and drive the disease process. PA stiffening constitutes an emerging research area in PH, with relevance in PH diagnostics, prognostics, and as a therapeutic target. With respect to its prognostic value, PA stiffness rivals the well-established measurement of pulmonary vascular resistance as a predictor of disease outcome. Vascular remodeling of the arterial extracellular matrix (ECM) as well as vascular calcification, smooth muscle cell stiffening, vascular wall thickening, and tissue fibrosis contribute to PA stiffening. While associations between inflammation and vascular stiffening are well-established in systemic vascular diseases such as atherosclerosis or the vascular manifestations of systemic sclerosis, a similar connection between inflammatory processes and PA stiffening has so far not been addressed in the context of PH. In this review, we discuss potential links between inflammation and PA stiffening with a specific focus on vascular calcification and ECM remodeling in PH.

Comparison of cytokine mediators in type 2 inflammatory conditions on the skin and ocular surface.

As the conjunctiva is embryologically modified skin, ocular surface involvement can be observed in several atopic skin diseases. The purpose of this review is to highlight and compare the roles of type 2 cytokines in the skin and ocular surface, and their resulting disorders. Although there have been extensive studies identifying various type 2 cytokine pathways in the skin, there is limited analyses of pathways assessed on the ocular surface. We provide the potential overlapping cytokine impacts on the skin and eye including interleukin (IL)-4, IL-5 IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP), and IL-31 that may provide important immunomodulatory interventions and treatment for the more chronic and sight-threatening ocular disorders. Dysregulation of type 2 inflammatory cytokines was found to elicit similar immunopathogenic responses on the skin and ocular surfaces, leading to barrier dysfunction, remodeling, immune cell recruitment, and symptoms such as pruritus.

Communication in non-communicable diseases (NCDs) and role of immunomodulatory nutraceuticals in their management

Conveyance of pathogens between organisms causes communicable diseases. On the other hand, a non-communicable disease (NCD) was always thought to have no causative transmissible infective agents. Today, this clear distinction is increasingly getting blurred and NCDs are found to be associated with some transmissible components. The human microbiota carries a congregation of microbes, the majority and the most widely studied being bacteria in the gut. The adult human gut harbors ginormous inhabitant microbes, and the microbiome accommodates 150-fold more genes than the host genome. Microbial communities share a mutually beneficial relationship with the host, especially with respect to host physiology including digestion, immune responses, and metabolism. This review delineates the connection between environmental factors such as infections leading to gut dysbiosis and NCDs and explores the evidence regarding possible causal link between them. We also discuss the evidence regarding the value of appropriate therapeutic immunomodulatory nutritional interventions to reduce the development of such diseases. We behold such immunomodulatory effects have the potential to influence in various NCDs and restore homeostasis. We believe that the beginning of the era of microbiota-oriented personalized treatment modalities is not far away.

The immune responses to different Uropathogens call individual interventions for bladder infection.

Urinary tract infection (UTI) caused by uropathogens is the most common infectious disease and significantly affects all aspects of the quality of life of the patients. However, uropathogens are increasingly becoming antibiotic-resistant, which threatens the only effective treatment option available-antibiotic, resulting in higher medical costs, prolonged hospital stays, and increased mortality. Currently, people are turning their attention to the immune responses, hoping to find effective immunotherapeutic interventions which can be alternatives to the overuse of antibiotic drugs. Bladder infections are caused by the main nine uropathogens and the bladder executes different immune responses depending on the type of uropathogens. It is essential to understand the immune responses to diverse uropathogens in bladder infection for guiding the design and development of immunotherapeutic interventions. This review firstly sorts out and comparatively analyzes the immune responses to the main nine uropathogens in bladder infection, and summarizes their similarities and differences. Based on these immune responses, we innovatively propose that different microbial bladder infections should adopt corresponding immunomodulatory interventions, and the same immunomodulatory intervention can also be applied to diverse microbial infections if they share the same effective therapeutic targets.

Systemic Immune Modulation Alters Local Bone Regeneration in a Delayed Treatment Composite Model of Non-Union Extremity Trauma.

Bone non-unions resulting from severe traumatic injuries pose significant clinical challenges, and the biological factors that drive progression towards and healing from these injuries are still not well understood. Recently, a dysregulated systemic immune response following musculoskeletal trauma has been identified as a contributing factor for poor outcomes and complications such as infections. In particular, myeloid-derived suppressor cells (MDSCs), immunosuppressive myeloid-lineage cells that expand in response to traumatic injury, have been highlighted as a potential therapeutic target to restore systemic immune homeostasis and ultimately improve functional bone regeneration. Previously, we have developed a novel immunomodulatory therapeutic strategy to deplete MDSCs using Janus gold nanoparticles that mimic the structure and function of antibodies. Here, in a preclinical delayed treatment composite injury model of bone and muscle trauma, we investigate the effects of these nanoparticles on circulating MDSCs, systemic immune profiles, and functional bone regeneration. Unexpectedly, treatment with the nanoparticles resulted in depletion of the high side scatter subset of MDSCs and an increase in the low side scatter subset of MDSCs, resulting in an overall increase in total MDSCs. This overall increase correlated with a decrease in bone volume (P = 0.057) at 6 weeks post-treatment and a significant decrease in mechanical strength at 12 weeks post-treatment compared to untreated rats. Furthermore, MDSCs correlated negatively with endpoint bone healing at multiple timepoints. Single cell RNA sequencing of circulating immune cells revealed differing gene expression of the SNAb target molecule S100A8/A9 in MDSC sub-populations, highlighting a potential need for more targeted approaches to MDSC immunomodulatory treatment following trauma. These results provide further insights on the role of systemic immune dysregulation for severe trauma outcomes in the case of non-unions and composite injuries and suggest the need for additional studies on targeted immunomodulatory interventions to enhance healing.

Rationale, design, and methods: A randomized placebo-controlled trial of an immunomodulatory probiotic intervention for Veterans with PTSD

BackgroundUnited States military Veterans from recent conflicts are experiencing symptoms related to posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy). Alternative treatment approaches are needed. An underlying feature of PTSD is exaggerated inflammation, both peripherally and in the central nervous system. This inflammation is thought to play an important role in the vulnerability to, aggravation of, and persistence of PTSD symptoms. Therefore, an innovative intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. Here we describe the rationale, design, and methods of a randomized placebo-controlled trial (RCT) of Lactobacillus rhamnosus GG (LGG; ATCC 53103) for posttraumatic stress disorder (PTSD). MethodsThis is a Phase IIa trial of LGG for United States military Veterans with PTSD, using a longitudinal, double-blind, randomized placebo-controlled design. The primary outcome measure is plasma concentration of high-sensitivity C-reactive protein. ConclusionDespite the fact that symptoms associated with PTSD can be disabling, individuals living with this trauma-related disorder have limited options in terms of evidence-based interventions. Recent research efforts aimed at highlighting the biological mechanisms of PTSD suggest that increased inflammation and altered autonomic nervous system activity may be treatment targets, and that immunoregulatory probiotics, such as LGG, have the potential to decrease trauma-induced inflammatory responses, as well as associated symptoms. This manuscript describes the best powered human subjects Phase IIa trial, to date, of a probiotic intervention for those living with PTSD.

A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics.

A mouse model of cutaneous leishmaniasis (CL) by Leishmania (Viannia) panamensis (L(V)p) that reproduces the characteristics of the human disease remains elusive. Here we report the development of a CL model that uses a mouse-adapted L(V)p isolate to reproducibly induce a dermal disease with a remarkable similarity to human CL. BALB/c mice infected intradermally in the ear with 105 stationary UA-946 L(V)p promastigotes develop a progressive cutaneous disease that exhibits the typical ulcerated lesions with indurated borders observed in CL patients. Although most of parasites in the inoculum die within the first week of infection, the survivors vigorously multiply at the infection site during the following weeks, paralleling disease appearance and aggravation. Regional lymphadenopathy as well as lymphatic dissemination of parasites to draining lymph nodes (dLN) was evidenced early after infection. Viable parasites were also isolated from spleen at later timepoints indicating systemic parasitic dissemination, but, strikingly, no signs of systemic disease were observed. Increasing numbers of myeloid cells and T lymphocytes producing IFNγ and IL-4 were observed in the dLN as disease progressed. A mixed adaptive L(V)p-specific T cell-mediated response was induced, since ex vivo recall experiments using dLN cells and splenocytes revealed the production of type 1 (IFNγ, IL-2), type 2 (IL-4, IL-13), regulatory (IL-10), and inflammatory (GM-CSF, IL-3) cytokines. Humoral adaptive response was characterized by early production of IgG1- followed by IgG2a-type of L(V)p-specific antibodies. IFNγ/IL-4 and IgG2a/IgG1 ratios indicated that the initial non-protective Th2 response was redirected toward a protective Th1 response. In situ studies revealed a profuse recruitment of myeloid cells and of IFNγ- and IL-4-producing T lymphocytes to the site of infection, and the typical histopathological changes induced by dermotropic Leishmania species. Evidence that this model is suitable to investigate pharmacological and immunomodulatory interventions, as well as for antigen discovery and vaccine development, is also presented. Altogether, these results support the validity and utility of this novel mouse model to study the pathogenesis, immunity, and therapeutics of L(V)p infections.

Lessons to Learn from the Gut Microbiota: A Focus on Amyotrophic Lateral Sclerosis

The gut microbiota is able to modulate the development and homeostasis of the central nervous system (CNS) through the immune, circulatory, and neuronal systems. In turn, the CNS influences the gut microbiota through stress responses and at the level of the endocrine system. This bidirectional communication forms the “gut microbiota–brain axis” and has been postulated to play a role in the etiopathology of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Numerous studies in animal models of ALS and in patients have highlighted the close communication between the immune system and the gut microbiota and, therefore, it is possible that alterations in the gut microbiota may have a direct impact on neuronal function and survival in ALS patients. Consequently, if the gut dysbiosis does indeed play a role in ALS-related neurodegeneration, nutritional immunomodulatory interventions based on probiotics, prebiotics, and/or postbiotics could emerge as innovative therapeutic strategies. This review aimed to shed light on the impact of the gut microbiota in ALS disease and on the use of potential nutritional interventions based on different types of biotics to ameliorate ALS symptoms.

Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell– and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFβ1). Blocking TGFβ signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell–stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy

Sepsis-associated encephalopathy (SAE) is a diffuse central nervous system (CNS) dysfunction during sepsis, and is associated with increased mortality and poor outcomes in septic patients. Despite the high incidence and clinical relevance, the exact mechanisms driving SAE pathogenesis are not yet fully understood, and no specific therapeutic strategies are available. Regulatory T cells (Tregs) have a role in SAE pathogenesis, thought to be related with alleviation of sepsis-induced hyper-inflammation and immune responses, promotion of T helper (Th) 2 cells functional shift, neuroinflammation resolution, improvement of the blood-brain barrier (BBB) function, among others. Moreover, in a clinical point of view, these cells have the potential value of improving neurological and psychiatric/mental symptoms in SAE patients. This review aims to provide a general overview of SAE from its initial clinical presentation to long-term cognitive impairment and summarizes the main features of its pathogenesis. Additionally, a detailed overview on the main mechanisms by which Tregs may impact SAE pathogenesis is given. Finally, and considering that Tregs may be a novel target for immunomodulatory intervention in SAE, different therapeutic options, aiming to boost peripheral and brain infiltration of Tregs, are discussed.

Tocilizumab and COVID-19: Timing of Administration and Efficacy.

Elevated concentrations of interleukin-6 have been demonstrated to be an important key factor in COVID-19 host immune impairment. It represents an important prognostic factor of harm associated with COVID-19 infection by stimulating a vigorous proinflammatory response, leading to the so-called “cytokine storm”. Therefore, immunomodulatory interventions targeting interleukin-6 receptor antagonism have been investigated as potential treatments to counterbalance the host immune dysregulation and to support the advantageous effects of corticosteroids. Tocilizumab is a recombinant humanized monoclonal antibody that has gained much interest during the COVID-19 pandemic as an interleukin-6 receptor antagonist. Various early observational studies have reported beneficial effects of tocilizumab. Moreover, consequent randomized controlled trials have subsequently shown significant positive results about tocilizumab efficacy and safety, focusing on outcomes like mortality, risk of intensive care unit admission, and the need for mechanical ventilation, while others presented conflicting findings. In this review, we first described the pathophysiology of COVID-19 infection while highlighting the role of interleukin-6. Furthermore, we also discussed the non-conclusive evidence about tocilizumab to be used as the standard of care therapy for all patients with COVID-19 pneumonia, as well as its beneficial effects in selected patients.