Adaptive Immune Cells Research Articles

Immune-Mediated Liver Injury From Checkpoint Inhibitor: An Evolving Frontier With Emerging Challenges.

Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the treatment of cancer, though they come with the risk of immune-related adverse (irAEs) events such as hepatotoxicity or Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation of ICI and initiation of immunosuppression. Cytotoxic T Lymphocytes (CTLs) play a central role in ILICI; however, they are just part of the picture as immunotherapy broadly impacts all aspects of the immune microenvironment and can directly and indirectly activate innate and adaptive immune cells. Clinically, as our understanding of this entity grows, we encounter new challenges. The presentation of ILICI is heterogeneous with respect to latency, pattern of injury (hepatitis vs. cholangitis) and severity. This review focuses on our knowledge regarding risk factors, presentation and treatment of ILICI including ILICI refractory to steroids. An emerging topic, the possibility of rechallenge while accepting some risk, in patients who experience ILICI but require immunotherapy, is also discussed. This review provides an update on the current knowns and unknowns in ILICI and highlights several knowledge gaps where studies are needed.

Regulatory Immune Cell-derived Exosomes: Modes of Action and Therapeutic Potential in Transplantation.

Reduced dependence on antirejection agents, improved long-term allograft survival, and induction of operational tolerance remain major unmet needs in organ transplantation due to the limitations of current immunosuppressive therapies. To address this challenge, investigators are exploring the therapeutic potential of adoptively transferred host- or donor-derived regulatory immune cells. Extracellular vesicles of endosomal origin (exosomes) secreted by these cells seem to be important contributors to their immunoregulatory properties. Twenty years ago, it was first reported that donor-derived exosomes could extend the survival of transplanted organs in rodents. Recent studies have revealed that regulatory immune cells, such as regulatory myeloid cells (dendritic cells, macrophages, or myeloid-derived suppressor cells), regulatory T cells, or mesenchymal stem/stromal cells can suppress graft rejection via exosomes that express a cargo of immunosuppressive molecules. These include cell surface molecules that interact with adaptive immune cell receptors, immunoregulatory enzymes, and micro- and long noncoding RNAs that can regulate inflammatory gene expression via posttranscriptional changes and promote tolerance through promotion of regulatory T cells. This overview analyzes the diverse molecules and mechanisms that enable regulatory immune cell-derived exosomes to modulate alloimmunity and promote experimental transplant tolerance. We also discuss the potential benefits and limitations of their application as therapeutic entities in organ transplantation.

Recent Advances on Immunity and Hypertension: The New Cells on the Kidney Block.

Over the last 50 years, contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that innate and adaptive immune cells, along with their cytokines and chemokines, modulate blood pressure fluctuations and end organ renal damage. Numerous cell types of the innate immune system, specifically monocytes, macrophages, and dendritic cells present antigenic peptides to T cells promoting inflammation and the elevation of blood pressure. These T cells and other adaptive immune cells, migrate to vascular and tubular cells of the kidney and promote end-organ fibrosis, damage, and ultimately hypertensive injury. Through the development of high throughput screening, novel renal and immune cell subsets have been identified as possible contributors and regulators of renal injury and hypertension. In this review, we will consider classical immunological cells and their contribution to renal inflammation, and novel cell subsets, including renal stromal cells, that could potentially shed new light on renal injury and hypertension. Lastly, we will discuss how interorgan inflammation contributes to the development of hypertension and hypertension-related multi-organ damage, and the clinical implications of the immunological components of renal injury and hypertension.

Early-Life Antibiotic Exposures: Paving the Pathway for Dysbiosis-Induced Disorders.

Microbiota encompasses a diverse array of microorganisms inhabiting specific ecological niches. Gut microbiota significantly influences physiological processes, including gastrointestinal motor function, neuroendocrine signalling, and immune regulation. They play a crucial role in modulating the central nervous system and bolstering body defence mechanisms by influencing the proliferation and differentiation of innate and adaptive immune cells. Given the potential consequences of antibiotic therapy on gut microbiota equilibrium, there is a need for prudent antibiotic use to mitigate associated risks. Observational studies have linked increased antibiotic usage to various pathogenic conditions, including obesity, inflammatory bowel disease, anxiety-like effects, asthma, and pulmonary carcinogenesis. Addressing dysbiosis incidence requires proactive measures, including prophylactic use of β-lactamase drugs (SYN-004, SYN-006, and SYN-007), hydrolysing the β-lactam in the proximal GIT for maintaining intestinal flora homeostasis. Prebiotic and probiotic supplementations are crucial in restoring intestinal flora equilibrium by competing with pathogenic bacteria for nutritional resources and adhesion sites, reducing luminal pH, neutralising toxins, and producing antimicrobial agents. Faecal microbiota transplantation (FMT) shows promise in restoring gut microbiota composition. Rational antibiotic use is essential to preserve microflora and improve patient compliance with antibiotic regimens by mitigating associated side effects. Given the significant implications on gut microbiota composition, concerted intervention strategies must be pursued to rectify and reverse the occurrence of antibiotic-induced dysbiosis. Here, antibiotics-induced microbiota dysbiosis mechanisms and their systemic implications are reviewed. Moreover, proposed interventions to mitigate the impact on gut microflora are also discussed herein.

Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits.

Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability. We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral flow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches. We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout. This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our findings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280.

Alcohol Consumption and Autoimmune Diseases.

Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune system's regulatory mechanisms to avoid attacking the body's tissues, it has been proven to play a dichotomic role in autoimmune diseases (ADs) based on the quantity of consumption. In this review, we report updated evidence on the role of alcohol in ADs, with a focus on alcohol addiction and the human biological immune system and the relationship between them, with alcohol as a risk or protective factor. Then, in this narrative review, we report the main evidence on the most studied ADs where alcohol represents a key modulator, including autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, diabetes, allergic rhinitis, and primary biliary cholangitis. Alcohol at low-moderate dosages seems mostly to have a protective role in these diseases, while at higher dosages, the collateral risks surpass possible benefits. The specific mechanisms by which low-to-moderate alcohol intake relieves AD symptoms are not yet fully understood; however, emerging studies suggest that alcohol may have a systemic immunomodulatory effect, potentially altering the balance of anti-inflammatory innate and adaptive immune cells, as well as cytokines (via the NF-κB or NLRP3 pathways). It might influence the composition of the gut microbiome (increasing amounts of beneficial gut microbes) and the production of their fatty acid metabolites, such as short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs), as well as elevated concentrations of acetate, high-density lipoprotein (HDL), and nitric oxide (NO). Unfortunately, a definite acceptable daily intake (ADI) of ethanol is complicated to establish because of the many mechanisms associated with alcohol consumption such that despite the interesting content of these findings, there is a limit to their applicability and risks should be weighed in cases of alcoholic drinking recommendations. The aim of future studies should be to modulate those beneficial pathways involved in the alcohol-protective role of ADs with various strategies to avoid the risks associated with alcohol intake.

Epigenetic Regulation of Innate and Adaptive Immune Cells in Salt-Sensitive Hypertension.

Access to excess dietary sodium has heightened the risk of cardiovascular diseases, particularly affecting individuals with salt sensitivity of blood pressure. Our research indicates that innate antigen-presenting immune cells contribute to rapid blood pressure increases in response to excess sodium intake. Emerging evidence suggests that epigenetic reprogramming, with subsequent transcriptional and metabolic changes, of innate immune cells allows these cells to have a sustained response to repetitive stimuli. Epigenetic mechanisms also steer T-cell differentiation in response to innate immune signaling. Immune cells respond to environmental and nutritional cues, such as salt, promoting epigenetic regulation changes. This article aims to identify and discuss the role of epigenetic mechanisms in the immune system contributing to salt-sensitive hypertension.

EXamining the feasibility of exerCisE to manage symptoms of Lupus (EXCEL): a protocol for a randomised controlled pilot study

IntroductionSLE is a chronic autoimmune disease that results in sustained hyperactivation of innate and adaptive immune cells and widespread inflammatory damage. Regular exercise reduces SLE symptoms including fatigue and joint...

Emerging role of adaptive immunity in diabetes-induced cognitive impairment: from the periphery to the brain.

Diabetic cognitive impairment (DCI) is a central nervous system complication induced by peripheral metabolic dysfunction of diabetes mellitus. Cumulative studies have shown that neuro-immune crosstalk is involved in the pathological progression of DCI. However, current studies mostly focus on the interaction between innate immunity cells and neurons, while ignoring the role of adaptive immunity cells in DCI. Notably, recent studies have revealed adaptive immune cells are involved in cognitive development and the progression of neurodegenerative diseases. Equally important, accumulated past studies have also shown that diabetic patients experience imbalanced peripheral adaptive immune homeostasis and disrupted transmission of adaptive immune cells to the central system. Therefore, this review first updated the cognitive mechanism of adaptive immune regulation, and then summarized the contribution of adaptive immunity to DCI from the aspects of peripheral adaptive immune homeostasis, transmission pathways, and brain tissue infiltration. Furthermore, we also summarized the potential of anti-diabetic drugs to regulate adaptive immunity, and looked forward to the potential value of regulatory adaptive immunity in the prevention and treatment of DCI, to provide a new strategy for the prevention and treatment of DCI.

Nutritional Interventions for Aging: Vitamin E and Selenium Impact on Immune Function

Elderly mortality as well as morbidity have been affected by immune-senescence, or immune system ageing. Age-related quantitative and qualitative shifts affect innate and adaptive immune responses, innate and adaptive immune cells, soluble immune-mediated substances, lymphoid and non-lymphoid distant tissue, etc. The thymus gland, which is an essential organ of the immune system responsible to produce T lymphocytes, begins to shrink after puberty and continues to do so as a person ages. This process is known as thymic involution. As the thymus gland becomes smaller and less active, the production of new T cells declines, and the existing T cells become less effective. This can lead to a weaker immune response to infections and disease. However, antigen-presenting cells and B cells are less affected because they are not produced in the thymus gland. Other factors such as chronic inflammation, stress, poor diet, and lack of exercise can also contribute to age-related immune decline. It’s important to maintain a healthy lifestyle and take steps to boost the immune system as one gets older.

Adaptive immune cells antagonize ILC2 homeostasis via SLAMF3 and SLAMF5.

Type 2 innate lymphoid cells (ILC2s) mainly reside in tissues with few lymphoid cells. How their tissue residency is regulated remains poorly understood. This study explores the inhibitory role of SLAM-family receptors (SFRs) on adaptive immune cells in ILC2 maintenance. We observed an increase in the population of ILC2s in Rag1-deficient mice. Homotypic engagement of SFRs between ILC2s and adaptive immune cells was identified as a potential mechanism. SFR deficiency led to an increase in ILC2s. Conditional deletion of SFRs on T and/or B cells led to an increased ILC2 abundance. Mechanistically, as ILC precursors differentiate into ILC2s, SFRs, primarily SLAMF3 and SLAMF5, are inhibitory, which impair IL-7-induced PI3K activation and enhance apoptosis via SHP-1. These findings reveal a mechanism by which adaptive immune cells negatively regulate the homeostasis of ILC2s and contribute to our understanding of the complex interplay between innate and adaptive immune cells in the regulation of immune responses.

Differences in immune cells and gene expression in human milk by parity on integrated scRNA sequencing.

Human breast milk (HBM) is an important source of tolerogenic immune mediators that influence the infant immune system. HBM-derived immune components are affected by various factors; however, few studies have examined the relationship between parity and immune cell profiles of HBM. This study aimed to clarify the effects of parity on HBM immune cell heterogeneity and gene expression by integrating and analyzing publicly available single-cell RNA sequencing datasets. The proportion of innate immune cells was significantly higher in the primiparous versus multiparous group, whereas the proportion of adaptive immune cells was significantly higher in the multiparous group (p = 0.021). The two immune clusters were re-annotated and classified into monocyte, T/B cell, and CD45 groups. The proportions of monocytes and T/B cells were higher in the primiparous and multiparous groups, respectively. In a gene set enrichment analysis of monocytes, genes with a direct role in the infant immune system and immune response-related genes were more highly expressed in the primiparous group. Our results support the parity-dependent differences in gene expression between innate and adaptive immune cells.

Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner.

Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cells response can lead to chronic neurodegeneration and functional deficits. Therefore, understanding the dynamic interaction between chronic immune responses and TBI-related pathogenesis and progression of the disease is crucial. We hypothesized that T cells have an essential role in TBI severity and recovery. We used generic T cell deletion mice (TCRβ-/-δ-/-) vs Wild-type mice that underwent to controlled cortical impact assessing behavioral, histological, and immune system response outcomes at 3 months post-TBI. The absence of T cells reduced neurodegeneration and was associated with improved neurological outcomes 3 months post-injury. Furthermore, the absence of T cells enhanced an anti-inflammatory phenotype in peripheral myeloid cells in the injured brain. Collectively, these data indicate that T cells promote persistent neuropathology and functional impairments chronically after TBI.

Nanostructured lipid carriers based mRNA vaccine leads to a Tcell-inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour model.

mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidots®, for delivering unmodified mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumour responses. We evaluated whether NLC OVA mRNA complexes activate dendritic cells (DCs) invitro and identified the involved signalling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in B16-OVA and E.G7-OVA cold tumour-bearing C57Bl6 female mice as well as its synergy effect with an anti-PD-1 therapy by following the tumour growth and performing immunophenotyping of innate and adaptive immune cells. The intratumoral vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumour cells. Our vaccine activates DCs invitro through the TLR4/8 and ROS signalling pathways and induces specific Tcell activation while exhibits significant preventive and therapeutic antitumour efficacy invivo. A profound intratumoral remodelling of the innate and adaptive immunity in association with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction were observed in immunised mice. The combination of vaccine and anti-PD-1 therapy improves the rates of complete responses and memory immune responses compared to monotherapies. Lipidots® are effective platform for the development of vaccines against cancer based on mRNA delivery. Their combination with immune checkpoint blockers could counter tumour resistance and promote long-term antitumour immunity. This work was supported by Inserm Transfert, la Région Auvergne Rhône Alpes, FINOVI, and the French Ministry of Higher Education, research and innovation (LipiVAC, COROL project, funding reference N° 2102992411).

Gene-gene interactions of cytokines and C-reactive protein in psoriasis in residents of Kemerovo region

Psoriasis is the most common inflammatory skin disease, affecting on average 2-4% of the world’s population. Currently, psoriasis is considered a multifactorial disease occurring in genetically predisposed individuals under the influence of various environmental factors that trigger a disrupted immune response via complex inflammatory cascades. The disease is initiated and maintained by the mutual interaction of cells of innate and adaptive immunity, primarily, dendritic cells, T lymphocytes and keratinocytes. Their leading role may alternate at different stages of the disease and proceeds, mainly, at the IL-23/Th17 pathway. To date, many gene polymorphisms (SNPs) associated with the development of psoriasis have been described. To understand the pathophysiology of psoriasis as a complex autoinflammatory disease, it seems interesting to study the intergenic interactions between polymorphic gene variants of cytokines and C-reactive protein related to the risk of psoriasis development. The aim of our study was to investigate intergenic interactions of polymorphic variants of IL1β (rs16944), IL6 (rs1554606), IL8 (rs2227306), IL10 (rs1800896), TNFα (rs361525), CRP (rs1205) genes associated with altered risk of psoriasis development among the Kemerovo Region residents. We examined 175 patients with ordinary papular plaque psoriasis of moderate severity, with progressive course of the disorder. The control group (n = 155) was recruited from conditionally healthy, age-matched donors. Genotyping was performed by PCR using TaqMan probes (Thermo Fisher Scientific, USA), by means of the detection amplifier ViiATM 7 Real-Time PCR System (Life Technologies, USA), for the following polymorphic variants of genes: IL1β (rs16944), IL6 (rs1554606), IL8 (rs2227306), IL10 (rs1800896), TNFα (rs361525), CRP (rs1205). Intergenic interactions were analyzed using Multifactor Dimensionality Reduction (MDR). The common papulosis-plaque psoriasis was found to be associated with individual polymorphic variants of cytokine and CRP genes as well as with gene-gene interactions. Concerning individual polymorphic gene variants, the association strength (% entropy) with common papulosis-plaque psoriasis was as follows: TNFα_ rs361525 (16.99% entropy), IL1β_rs16944 (6.40% entropy), CRP_rs1205 (2.55% entropy), IL6_rs1554606 (1.11% entropy), IL10_rs1800896 (0.57% entropy), IL8_rs2227306 (0.30% entropy). We have found that IL6 (rs1554606) and IL8 (rs2227306) showed marked synergism, as well as moderate synergism of CRP (rs1205) and IL10 (rs1800896), and pronounced antagonism of IL1β (rs16944) and TNFα (rs361525).

Adaptive ımmune system evaluation in familial mediterranean fever: clinical and ımmunological analysis.

Familial Mediterranean Fever is a common genetic autoinflammatory disease prevalent in the Mediterranean region. The clinical course of the disease is characterized by fever and serositis attacks. While defects in the innate immune system are known to play a role in the pathogenesis of the disease, the impact of the adaptive immune system remains unclear. Therefore, the main objective of this study is to analyze the adaptive immune system cells in FMF patients and investigate their relationship with the disease. Our study includes 88 FMF patients with confirmed MEFV gene mutations. The demographic characteristics, clinical symptoms, genetic profiles, treatment methods, and any accompanying diseases of the patients were thoroughly examined. Additionally, lymphocyte subpopulations were analyzed using flow cytometry, and inflammatory markers and immunoglobulin levels were evaluated. Significant differences were observed in the distribution of adaptive immune system cells in FMF patients compared to the healthy reference group. In the analysis of lymphocyte subgroups, levels of CD3, CD4, CD19, CD16+56+, CD3CD4CD45RACD31, CD4+CD45RA+, CD8+CD45RA+, CD19+CD27+IgD+IgM+, CD19+CD27+IgD-IgM-, and CD19+CD38+CD21 were found to be lower compared to healthy individuals. Additionally, CD8, CD19+CD27-IgD+, and CD3/CD8/TCRGD cells were found to be higher. Moreover, in FMF patients with accompanying diseases, CD3, CD4, and CD19 values were statistically lower (p<0.001). This study reveals that adaptive immune system cells are affected in FMF patients, suggesting their significant role in the disease's pathophysiology. Immunological evaluations should be prioritized in the management of FMF, enabling personalized treatment plans for more effective outcomes.

Norepinephrine promotes activated B cells to identify and kill effector CD8+ T cells through FasL/Fas pathway in spleen mononuclear cells isolated from experimental autoimmune encephalomyelitis.

It has been reported that the nervous system can regulate immune reactions through various mechanisms. However, the role of splenic sympathetic nerve activity in the autoimmune reactions during the pathogenesis of experimental autoimmune encephalomyelitis (EAE) remained unclear. Here, we blocked the activity of the splenic sympathetic nerve and found that the number of adaptive immune cells, such as CD4+ T cells, CD8+ T cells and B cells, were upregulated. Additionally, there was an increase in the secretion of inflammatory cytokines in the spleen, and the neurological symptoms of EAE were exacerbated. In vitro experiments, we found that norepinephrine (NE), the neurotransmitter of the splenic sympathetic nerve, indirectly drove the death of effector CD8+ T cells. Furthermore, activated B cells, under the influence of NE, specifically recognized effector CD8+ T cells by upregulating MHC-I molecules and killed these cells via the FasL/Fas pathway. Our findings provide a new perspective on B cells killing effect in vitro, which was boosted by NE and demonstrate that the splenic sympathetic nerve controls the degree of autoimmune responses in EAE. This adds a new dimension to the diversity of NE's regulatory effects on adaptive immune cells and suggests a potential new therapeutic approach for autoimmune diseases.

Mast cells and arteriogenesis: A systematic review.

Vascular occlusive diseases remain a major health burden worldwide, necessitating a deeper understanding of the adaptive responses that mitigate their impact. Arteriogenesis, the growth and remodeling of collateral vessels in response to arterial occlusion, is a vital defense mechanism that counteracts fluid shear stress-induced vascular stenosis or occlusion. While physical factors driving arteriogenesis have been extensively studied, the specific cellular mediators involved are poorly understood. Notably, the role of innate and adaptive immune cells, particularly mast cells, in arteriogenesis has received limited attention. This systematic review bridges this knowledge gap by investigating the contribution of mast cells to vascular cell proliferation and leukocyte recruitment in arteriogenesis. A comprehensive search of major databases using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines reveals the critical connection between mast cells, inflammatory cells, innate immune cells, and growth factors in arteriogenesis. Our findings highlight the molecular mechanisms of mast cell activation, sheer stress exertion, and pro-arteriogenic growth factor recruitment. Furthermore, we explore the endogenous and exogenous factors, including nitrite, dipyridamole, thrombin, and cobra venom, triggering mast cell-mediated release of pro-arteriogenic factors. Additionally, we examine the impact of recombinant parathyroid hormone (rPTH) therapy on mast cell numbers and arteriogenesis in bone defect and allograft healing. Our review provides compelling evidence for the pro-arteriogenic role of mast cells, particularly during the early inflammatory phase of vessel occlusion, suggesting that targeting mast cell activation may be a promising therapeutic strategy for enhancing arteriogenesis and treating ischemia-related diseases.

Exploring perinatal mesenchymal stromal cells as a potential therapeutic strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by inflammation in the synovial tissue, driven by aberrant activation of both the innate and adaptive immune systems, which can lead to irreversible disability. Despite the increasing therapeutic approaches for RA, only a low percentage of patients achieve sustained disease remission, and the persistence of immune dysregulation is likely responsible for disease recurrence once remission is attained. Cell therapy is an attractive, wide-spectrum strategy to modulate inflammation, and mesenchymal stromal cells (MSC) derived from perinatal tissues provide valuable tools for their use in regenerative medicine, mainly due to their immunomodulatory properties. Several in vitro studies have shown that perinatal MSC modulate the proliferation, maturation, and cytokine secretion profile of both innate and adaptive immune cells. Moreover, different beneficial effects have also been described when perinatal MSC were used to treat animal models of diseases associated with inflammatory conditions and degenerative processes. Specifically, in experimental models of RA, treatment with perinatal MSC resulted in a strong reduction of articular damage, which was associated with the modulation of both inflammation and activation of stromal resident cells in the synovial tissue. Here, we present in vitro and in vivo evidence supporting the use of perinatal MSC in RA. We also highlight the promising results from the few published clinical trials, which demonstrate the safety of perinatal MSC.

Identifying novel aging-related diagnostic and prognostic models and aging-targeted drugs for sepsis patients

Sepsis is defined as a dysfunctional, life-threatening response to infection leading to multiorgan dysfunction and failure. During the past decade, studies have highlighted the relationship between sepsis and aging. However, the role of aging-related mechanisms in the progression and prognosis of sepsis remains unclear. In the present study, we divided sepsis patients into High- and Low-aging groups based on the gene set variation analysis (GSVA) scores of GOBP-AGING gene set. Sepsis patients in the high-aging group exhibited higher levels of infiltration of innate immune cells, lower levels of infiltration of adaptive immune cells, and a worse prognosis than those in the Low-aging group. Additionally, the MPO to MME ratio (MPO/MME) appears to be an effective biomarker for predicting the prognosis of sepsis patients. Moreover, ARG1/SEC63 and ARG1/CDKN1C appear to be effective and robust biomarkers for the early diagnosis of sepsis patients. Finally, we found that thalidomide (TAL) significantly ameliorated LPS induced inflammation and organ injury and attenuated LPS induced cellular senescence in lung and kidney. Overall, this study provides new insights into the heterogeneity of sepsis, reveals the vital role of aging-related markers in the prognosis and diagnosis of sepsis and demonstrates that TAL is a novel aging-targeted drug for sepsis patients by attenuating LPS induced cellular senescence.