Experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin basic protein (MBP) is a self-limiting disease model of multiple sclerosis. CD4+CD25+Foxp3+T cells play a role in limiting autoimmune disease but treatment with antigen naïve CD4+CD25+ cells does not reduce EAE. This study examined if in vitro activation by MBP and rIL-2 induced CD4+CD25+Foxp3+ cells that could inhibit EAE. Culture of CD4+CD8-CD25+cells from naïve rats with MBP and rIL-2 induced activated Treg that reduced the severity of clinical EAE and infiltration of CD8+T cells and macrophage into brain stem. CD4+CD25+T cells activated by an irrelevant autoantigen and rIL-2 did not suppress EAE. Resting CD4+CD25+T cells activated by autoantigen and rIL-2 have mRNA for Infgr, Il12rb2, Il5 but not Tbet, Gata3, Ilr5ra or Ifng. These changes in mRNA expression are the markers of Ts1 cells. A proportion of CD4+CD8-CD25+ cells activated by MBP/rIL-2 were induced to express CD8α, CD8β and CD62L. Depletion of CD4+CD8α+CD25+ cells removed the capacity of MBP and rIL-2 activated CD4+CD25+T cells to suppress EAE. This study demonstrated that in vitro activation of CD4+CD8-CD25+ cells by MBP/rIL-2 induced relevant antigen-specific Treg within days, which expressed CD8α, CD8β and CD62L with a Ts1 phenotype and that had greater potency than freshly isolated antigen naive CD4+CD25+Treg in suppressing clinical severity of EAE and immune inflammation in CNS. These findings may guide development of antigen-specific Treg for therapy.

The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.

Inflammation is recognized as a pivotal factor in the pathophysiology of acute ischemic stroke (AIS) and has the potential to influence the collateral circulation of patients. The objective of this investigation was to explore the link between peripheral regulatory T cells (Tregs), interleukin-2 (IL-2), and the status of collateral circulation.

Between September 2023 and May 2024, the study incorporated 117 AIS patients from the neurology department, with 60 identified as having good collateral status (GCS) and 57 with poor collateral status (PCS). Additionally, a control group of 46 healthy individuals was included. Collateral circulation in AIS patients was assessed via computed tomography angiography. The levels of peripheral blood Tregs were quantified through flow cytometry, while IL-2 was measured by ELISA.

In this investigation, patients diagnosed with PCS demonstrated reduced Tregs (5.77 ± 1.55%) and IL-2 levels (7.37 ± 2.61 pg/mL) compared to individuals with GCS (7.09 ± 1.32%, 9.95 ± 3.58 pg/mL) and healthy controls (7.17 ± 1.40%,10.33 ± 4.01 pg/mL). Logistic regression analysis identified significant associations between Tregs and IL-2 levels and collateral circulation status (p<0.05), with diminished levels of both being independent predictors of PCS when compared to GCS. A nomogram was developed to forecast risk factors for collateral circulation, further highlighting the potential of plasma Tregs and IL-2 levels as biomarkers in predicting collateral circulation among AIS patients. The diagnostic performance of Tregs and IL-2 was assessed utilizing receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) for Tregs in differentiating GCS from PCS patients was ascertained to be 0.741 (95% confidence interval [CI]: 0.652-0.830), while for IL-2, it was 0.710 (95% CI: 0.618-0.803). Moreover, the combined measurement of Tregs and IL-2 resulted in an AUC of 0.779 (95% CI: 0.695-0.863).

Plasma levels of peripheral blood Tregs and IL-2 may function as promising biomarkers for the prediction of collateral circulation status, suggesting potential new therapeutic approaches aimed at enhancing cerebral collateral circulation, and providing new therapeutic targets for acute ischemic stroke.

Klotho deficiency is prevalent in various chronic kidney diseases. Although klotho is known to bind transforming growth factor β (TGFβ) receptor 1 to antagonize renal fibrosis, TGFβ also maintains regulatory T cells with inducing forkhead box protein P3 (FOXP3). Female New Zealand Black/White F1 (NZBWF1) mice were divided into two groups (n = 10 for each): one group was treated with daily subcutaneous injection of klotho protein (30 μg/kg/day) for 8 weeks, and the other only received vehicle. Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2α excretion, albuminuria, and renal angiotensin II levels (p < 0.05 for all) without affecting the glomerular filtration rate (GFR) in NZBWF1 mice. Klotho protein supplementation reduced the number of cluster of differentiation (CD)4+FOXP3+ T cells (p < 0.05) without altering the anti-DNA antibody levels. Klotho supplementation augmented glomerular cellularity, but decreased glomerular crescent formation and interstitial fibrosis in NZBWF1 mice (p < 0.05). Klotho protein supplementation inactivated renal renin-angiotensin system, ameliorating blood pressure and albuminuria in NZBWF1 mice. Klotho supplementation hampered regulatory T cells without altering autoantibodies, exerting dual effects on glomerular pathology in NZBWF1 mice without changes in GFR.

Based on previous research, it is well-established that myasthenia gravis (MG) is linked to chronic inflammation. However, the exact nature of the relationship between inflammatory factors and the development of MG remains unclear. Consequently, the objective of this study is to explore whether alterations in the levels of inflammatory factors, as influenced by genetic factors, are associated with the occurrence of MG. This will be achieved through a two-sample Mendelian randomization (MR) analysis.

We conducted a bidirectional Mendelian randomization (MR) study utilizing genetic data from genome-wide association studies (GWAS), encompassing 1873 MG cases and 36,370 individuals of European ancestry as controls. Data on inflammatory cytokines were obtained from GWAS data of 8293, healthy participants. The inverse variance-weighted (IVW) method was primarily employed to investigate the causal relationship between exposure and outcome. Additionally, various sensitivity analysis methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were applied to strengthen the reliability of the results. Through these rigorous approaches, we extensively examined the relationship between inflammatory factors and MG; however, further research is required to establish the specific causal relationship.

After applying Bonferroni correction, the genetic predictions revealed a significant correlation between Monokine induced by gamma interferon (MIG) and MG (OR: 1.09, 95 % CI: 1.04-1.14; P = 0.0006). Furthermore, there were preliminary findings indicating a positive genetic association between Eotaxin and interleukin-2 receptor antagonist (IL-2ra) with MG (OR: 0.81, 95 % CI: 0.66-0.99, P = 0.044; OR: 0.80, 95 % CI: 0.68-0.94, P = 0.008). Reverse MR analysis provided initial evidence of associations between MIP1α, GROa, IL-13, TRAIL, IL-2ra, and IL-1ra with the development of MG. No indications of pleiotropy or heterogeneity among genetic variants were observed (P > 0.05).

This study uncovers a new connection between inflammatory cytokines and MG, shedding light on potential factors contributing to the development of the disease. Elevated levels of Eotaxin and IL-2ra are associated with a higher risk of MG, while indicating that MIG, MIP1α, GROa, IL-13, TRAIL, IL-2ra, and IL-1ra may be elevated as a result of MG, Especially MIG. These findings suggest that targeting and regulating specific inflammatory factors could offer promising avenues for the treatment and prevention of MG.

Genetic engineering of regulatory T cells (Tregs) presents a promising avenue for advancing immunotherapeutic strategies, particularly in autoimmune diseases and transplantation. This study explores the modification of Tregs via mRNA electroporation, investigating the influence of T-cell activation status on transfection efficiency, phenotype, and functionality. For this CD45RA+ Tregs were isolated, expanded, and modified to overexpress brain-derived neurotrophic factor (BDNF). Kinetics of BDNF expression and secretion were explored. Treg activation state was assessed by checking the expression of activation markers CD69, CD71, and CD137. Our findings show that only activated Tregs secrete BDNF post-genetic engineering, even though both activated and resting Tregs express BDNF intracellularly. Notably, the mTOR pathway and CD137 are implicated in the regulation of protein secretion in activated Tregs, indicating a complex interplay of signalling pathways. This study contributes to understanding the mechanisms governing protein expression and secretion in engineered Tregs, offering insights for optimizing cell-based therapies and advancing immune regulation strategies.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by autonomic failure and motor impairment. The hallmark pathologic finding in MSA is widespread oligodendroglial cytoplasmic inclusions rich in aggregated α-synuclein (αSyn). MSA is widely held to be an oligodendroglial synucleinopathy, and we outline lines of evidence to support this assertion, including the presence of early myelin loss. However, we also consider emerging data that support the possibility of neuronal or immune dysfunction as a primary driver of MSA. These hypotheses are placed in the context of a major recent discovery that αSyn is conformationally distinct in MSA versus other synucleinopathies such as Parkinson's disease. We outline emerging techniques in epidemiology, genetics, and molecular pathology that will shed more light on this mysterious disease. We anticipate a future in which cutting-edge developments in personalized disease modeling, including with pluripotent stem cells, bridge mechanistic developments at the bench and real benefits at the bedside.

Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in the development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.

Teratomas are a highly differentiated type of testicular germ cell tumors (TGCTs), the most common type of solid cancer in young men. Prominent inflammatory infiltrates are a hallmark of TGCTs, although their compositions and dynamics in teratomas remain elusive. Here, we reached out to characterize the infiltrating immune cells and their activation and polarization state by using high-throughput gene expression analysis of 129.MOLF-Chr19 mice that spontaneously develop testicular teratomas. We showed that inconspicuous testes without any apparent alterations in size or morphology can be clustered into three groups based on their expression of stemness and immune genes, supporting a model in which initial oncogenic transformation elicits a first wave of T-cell infiltration. Moderately and severely enlarged tumorous testes then displayed a progressive infiltration with T cells, monocytes/macrophages, and B cells. Importantly, T cells seem to adopt an inactive state caused by an overexpression of immune checkpoint molecules and the polarization of monocytes/macrophages to an anti-inflammatory phenotype. Our findings are supported by the analysis of metabolic gene expression, which unveiled alterations indicative of tumor growth and immune cell infiltration. Collectively, testicular teratomas, at least in mice, are characterized by a diverse inflammatory infiltrate containing T cells that putatively become inactivated, allowing the tumors to further grow. We believe that these findings may provide a rationale for the development of new immunomodulatory therapies for TGCTs.

Immune checkpoint inhibitors, such as anti-PD-1 antibodies, represent a significant advancement in cancer immunotherapy, but their efficacy varies notably between individuals, influenced by complex biological systems. Recent evidence suggests that sex-related biological differences play a pivotal role in modulating these responses. This study uses a systems biology approach to examine how sex-specific differences in the immune system contribute to variability in the response to treatment. Our model extends previous frameworks by incorporating sex-specific parameters that reflect observed immunological distinctions. The results from the simulation studies align with our clinical observations, showing that on average, males exhibit a more robust response to anti-PD-1 treatment compared to females. Additionally, this study explores the potential of combination therapy with recombinant IL-12, revealing sex-specific differences in treatment efficacy. These findings underscore the need for personalized immunotherapy strategies that consider individual immunological profiles, including sex, to optimize treatment outcomes.

The high prevalence of drug resistance, relapse, and unfavorable response rate of conventional cancer therapies necessitate the development of more efficient treatment modalities. Immunotherapy represents a novel therapeutic approach to cancer treatment in which the immune system's potential is harnessed to recognize and eliminate tumor cells. mRNA cancer vaccines, as a burgeoning field of immunotherapy, have recently drawn particular attention, and among mRNAs encoding tumor-associated antigens, tumor-specific antigens, and immune stimulatory factors, the latter has been relatively less explored. These immunostimulatory mRNAs encode a range of proteins, including stimulatory ligands, receptors, enzymes, pro-inflammatory cytokines, and inhibitory binding proteins, which collectively augment the host immune system's ability against cancerous cells. In this review, we aimed to provide a comprehensive account of mRNA-based cancer vaccines encoding immune stimulants, encompassing their current status, mechanisms of action, delivery strategies employed, as well as recent advances in preclinical and clinical studies. The potential challenges, strategies and future perspectives have also been discussed.

The occurrence of acute kidney injury (AKI) is elevated, one of the main causes is ischemia-reperfusion (I/R). However, no specific therapy is currently available to treat I/R-induced AKI (I/R-AKI). Treg cells have been demonstrated to perform an anti-inflammatory role in a range of autoimmune and inflammatory illnesses. However, there is limited available information about the possible functions of CD8 + CD103 + iTregs in I/R-AKI. We utilized renal tubular epithelial cells (RTECs) subjected to hypoxia-reoxygenation (H/R) and I/R-AKI mouse model to investigate whether CD8 + CD103 + iTregs could attenuate AKI and the underlying mechanism. In vitro, co-cultured with CD8 + CD103 + iTregs alleviated H/R-induced cell injury. After treatment of CD8 + CD103 + iTregs rather than control cells, a significant improvement of I/R-AKI was observed in vivo, including decreased serum creatinine (sCr) and blood urea nitrogen (BUN) levels, reduced renal pathological injury, lowered tubular apoptosis and inhibition of the transition from AKI to chronic kidney disease (CKD). Mechanically, CD8 + CD103 + iTregs alleviated H/R-induced cell injury and I/R-AKI partly by suppressing RTECs pyroptosis via inhibiting the NLRP3/Caspase-1 axis. Our study provides a novel perspective on the possibility of CD8 + CD103 + iTregs for the treatment of I/R-AKI.

Treatment of autoimmunity and autoinflammation with regulatory T cells has received much attention in the last twenty years. Despite the well-documented clinical benefit of Treg therapy, a large-scale application has proven elusive, mainly due to the extensive culture facilities required and associated costs. A possible way to overcome these hurdles in part is to target Treg migration to inflammatory sites using a small molecule. Here we review recent advances in this strategy and introduce the new concept of pharmacologically enhanced delivery of endogenous Tregs to control inflammation, which has been recently validated in humans.

Spinal cord injury (SCI) results from various mechanisms that damage the nervous tissue and the blood-brain barrier, leading to sensory and motor function loss below the injury site. Unfortunately, current therapeutic approaches for SCI have limited efficacy in improving patients outcomes. Galectin-3, a protein whose expression increases after SCI, influences the neuroinflammatory response by favoring pro-inflammatory M1 macrophages and microglia, while inhibiting pro-regenerative M2 macrophages and microglia, which are crucial for inflammation resolution and tissue regeneration. Previous studies with Galectin-3 knock-out mice demonstrated enhanced motor recovery after SCI. The M1/M2 balance is strongly influenced by the predominant lymphocytic profiles (Th1, Th2, T Reg, Th17) and cytokines and chemokines released at the lesion site. The present study aimed to investigate how the absence of galectin-3 impacts the adaptive immune system cell population dynamics in various lymphoid spaces following a low thoracic spinal cord compression injury (T9-T10) using a 30 g vascular clip for one minute. It also aimed to assess its influence on the functional outcome in wild-type (WT)and Galectin-3 knock-out (GALNEG) mice. Histological analysis with hematoxylin-eosin and Luxol Fast Blue staining revealed that WT and GALNEG animals exhibit similar spinal cord morphology. The absence of galectin-3 does not affect the common neuroanatomy shared between the groups prompting us to analyze outcomes between both groups. Following our crush model, both groups lost motor and sensory functions below the lesion level. During a 42-day period, GALNEG mice demonstrated superior locomotor recovery in the Basso Mouse Scale (BMS) gait analysis and enhanced motor coordination performance in the ladder rung walk test (LRW) compared to WT mice. GALNEG mice also exhibited better sensory recovery, and their electrophysiological parameters suggested a higher number of functional axons with faster nerve conduction. Seven days after injury, flow cytometry of thymus, spleen, and blood revealed an increased number of T Reg and Th2 cells, accompanied by a decrease in Th1 and Th17 cells in GALNEG mice. Immunohistochemistry conducted on the same day exhibited an increased number of Th2 and T Reg cells around the GALNEG's spinal cord lesion site. At 42-day dpi immunohistochemistry analyses displayed reduced astrogliosis and greater axon preservation in GALNEG's spinal cord seem as a reduction of GFAP immunostaining and an increase in NFH immunostaining, respectively. In conclusion, GALNEG mice exhibited better functional recovery attributed to the milder pro-inflammatory influence, compensated by a higher quantity of T Reg and Th2 cells. These findings suggest that galectin-3 plays a crucial role in the immune response after spinal cord injury and could be a potential target for clinical therapeutic interventions.

Subarachnoid hemorrhage (SAH) was a stroke with high occurrence and mortality. At the early stage, SAH patients have severe cerebral injury which is contributed by inflammation. In this study, we aimed to explore the anti-inflammation effect of low-dose IL-2 in SAH mice.

The 12-week-old C57BL/6J male mice were conducted with SAH surgery (Internal carotid artery puncture method). Different dose of IL-2 was injected intraperitoneally for 1 h, 1 day, and 2 days after SAH. Single-cell suspension and flow cytometry were used for the test of regulatory T (Treg) cells. Immunofluorescence staining was used to investigate the phenotypic polarization of microglia and inflammation response around neurons. Enzyme-Linked Immuno-sorbent Assay (ELISA) was applied to detect the level of pro-inflammatory factors.

Low-dose IL-2 could enrich the Treg cells and drive the microglia polarizing to M2. The level of pro-inflammatory factors, IL-1α, IL-6, and TNF-α decreased in the low-dose IL-2 group. The inflammation response around neurons was attenuated. Low-dose IL-2 could increase the number of Treg cells, which could exert a neuroprotective effect against inflammation after SAH.

Low-dose IL-2 had the potential to be an effective clinical method to inhibit inflammation after SAH.

The inflammatory response plays an essential role in the tumor microenvironment (TME) of colorectal cancer (CRC) by modulating tumor growth, progression, and response to therapy through the recruitment of immune cells, production of cytokines, and activation of signaling pathways. However, the molecular subtypes and risk score prognostic model based on inflammatory response remain to be further explored.

Inflammation-related genes were collected from the molecular signature database and molecular subtypes were identified using nonnegative matrix factorization based on the TCGA cohort. We compared the clinicopathological features, immune infiltration, somatic mutation profile, survival prognosis, and drug sensitivity between the subtypes. The risk score model was developed using LASSO and multivariate Cox regression in the TCGA cohort. The above results were independently validated in the GEO cohort. Moreover, we explored the biological functions of the hub gene, receptor interacting protein kinase 2 (RIPK2), leveraging proteomics data, in vivo, and in vitro experiments.

We identified two inflammation-related subtypes (inflammation-low and inflammation-high) and have excellent internal consistency and stability. Inflammation-high subtype showed higher immune cell infiltration and increased sensitivity to common chemotherapeutic drugs, while inflammation-low subtype may be more suitable for immunotherapy. Besides, the two subtypes differ significantly in pathway enrichment and biological functions. In addition, the 11-gene signature prognostic model constructed from inflammation-related genes showed strong prognostic assessment power and could serve as a novel prognostic marker to predict the survival of CRC patients. Finally, RIPK2 plays a crucial role in promoting malignant proliferation of CRC cell validated by experiment.

This study provides new insights into the heterogeneity of CRC and provides novel opportunities for treatment development and clinical decision making.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

For decades, immunotherapies have offered hope for patients with advanced cancer. However, they show distinct benefits and limited clinical effects. Tumor vaccines have the potential to prime tumor-antigen-specific T cells and induce broad subsets of immune responses, ultimately eradicating tumor cells. Here, we classify tumor vaccines by their anti-tumor mechanisms, which include boosting the immune system, overcoming tumor immunosuppression, and modulating tumor angiogenesis. We focus on multidimensional tumor vaccine strategies using combinations of two or three of the above mechanisms, as these are superior to single-dimensional treatments. This review offers a perspective on tumor vaccine strategies and the future role of vaccine therapies in cancer treatment.

Microwave (MW) thermal therapy has been developed as an effective clinical strategy that can achieve pronounced antitumor activity and also has the potential to trigger antitumor immunity. However, patients generally face high rates of tumor recurrence following MW treatment, limiting the long-term benefits of such treatment. The combination of MW treatment and immunomodulatory strategies may represent a promising means of reprogramming the immunosuppressive tumor microenvironment (TME) in a manner conducive to lower recurrence rates. In this study, a Lenvatinib-loaded Gd/Fe metal-organic framework (Gd/FeMOF) was designed as a promising approach to enhancing such antitumor immunity. MW-enhanced dynamic Gd/FeMOF sensitization can facilitate high levels of reactive oxygen species production under MW irradiation, resulting in stronger immunogenic tumor cell death. In parallel, the Lenvatinib released from Gd/FeMOF preparations can serve as an immune adjuvant that suppresses programmed death ligand 1 (PD-L1) expression and drives the reprogramming of the immunosuppressive TME. The Gd and Fe present within this MOF preparation also imbue it with magnetic resonance imaging capabilities. Importantly, in vivo animal model experiments confirmed the ability of GdFeMOF treatment to significantly enhance antitumor immunity while protecting against recurrence. Accordingly, this study offers a foundation for promising strategies aimed at the integrated diagnosis and durable treatment of cancer. STATEMENT OF SIGNIFICANCE: High rates of tumor recurrence following MW thermal therapy limit the long-term benefits of such treatment. We found that the administration of Lenvatinib-loaded Gd/FeMOF nanoparticles significantly reduced tumor recurrence after MW thermal therapy. Under MW irradiation, the Gd/FeMOF nanoparticles were found to augment the immune response due to facilitation of the process of immunogenic cell death. In addition, the released Lenvatinib could act as an immune adjuvant to downregulate the expression of PD-L1 and reprogram the immunosuppressive state of the tumor microenvironment, thus further enhancing the immune response. This is significant because MW-induced immune responses are relatively weak and usually fail to effectively prevent tumor recurrence. The combination of MW treatment with an immunomodulatory strategy may solve this problem.

The 'immune risk profile' has been shown to predict mortality in the elderly, highlighting the need to better understand age-related immune dysfunction. While aging leads to many defects affecting all arms of the immune system, this review is focused on the accrual of immuno-suppressive CD4 + T cell populations, including FoxP3 + regulatory T cells, and subsets of IL-10-producing T follicular helper cells. New data suggest that such accumulations constitute feedback mechanisms to temper the ongoing progressive low-grade inflammation that develops with age, the so-called "inflammaging", and by doing so, how they have the potential to promote healthier aging. However, they also impair effector immune responses, notably to infections, or vaccines. These studies also reinforce the idea that the aged immune system should not be considered as a poorly functional version of the young one, but more as a dynamic system in which CD4 + T cells, and other immune/non-immune subsets, differentiate, interact with their milieu and function differently than in young hosts. A better understanding of these unique interactions is thus needed to improve effector immune responses in the elderly, while keeping inflammaging under control.

Regulatory T cells (Treg) are CD4+ T cells with immune-suppressive function, which is defined by Foxp3 expression. However, the molecular determinants defining the suppressive population of T cells have yet to be discovered. Here we report that the cell surface protein Lrig1 is enriched in suppressive T cells and controls their suppressive behaviors. Within CD4+ T cells, Treg cells express the highest levels of Lrig1, and the expression level is further increasing with activation. The Lrig1+ subpopulation from T helper (Th) 17 cells showed higher suppressive activity than the Lrig1- subpopulation. Lrig1-deficiency impairs the suppressive function of Treg cells, while Lrig1-deficient naïve T cells normally differentiate into other T cell subsets. Adoptive transfer of CD4+Lrig1+ T cells alleviates autoimmune symptoms in colitis and lupus nephritis mouse models. A monoclonal anti-Lrig1 antibody significantly improves the symptoms of experimental autoimmune encephalomyelitis. In conclusion, Lrig1 is an important regulator of suppressive T cell function and an exploitable target for treating autoimmune conditions.

The aim of this study was to evaluate baseline differences by HIV status and the impact of pomalidomide on lymphocyte counts and T-cell subsets in patients with Kaposi sarcoma.

We prospectively evaluated CD4 + and CD8 + T-cell phenotypes in 19 participants with Kaposi sarcoma enrolled on a phase 1/2 study of pomalidomide (NCT01495598), seven without HIV and 12 with HIV on antiretroviral therapy.

Trial participants received pomalidomide 5 mg orally for 21 days of 28-day cycles for up to 1 year. Flow cytometry was performed on peripheral blood mononuclear cells at baseline, after three cycles, and at end-of-treatment. Lymphocyte count and T-cell subset comparisons were evaluated by Wilcoxon signed-rank and Mann--Whitney tests.

At baseline, HIV + participants had lower CD4 + cell counts (median 416 vs. 742 CD4 + T cells/μl, P  = 0.006), and a decreased proportion of CD57 + (senescent) CD8 + T cells ( P  = 0.007) compared with HIV - participants. After three cycles, pomalidomide led to an increased proportion of CD45RO + CD27 + (central memory) CD4 + ( P  = 0.002) and CD8 + ( P  = 0.002) T cells, a decrease in CD45RO - CD27 - (effector) CD4 + cells ( P  = 0.0002), and expansion of CD38 + /HLADR + (activated) CD4 + ( P  = 0.002) and CD8 + ( P  ≤ 0.0001) T cells. Increased numbers of activated CD8 + T cells persisted at end-of-treatment ( P  = 0.002). After three cycles and at end-of-treatment, there was reduction in the proportion of CD57 + (senescent) CD4 + ( P  = 0.001, 0.0006), and CD8 + ( P  =  < 0.0001, 0.0004) T cells.

Administration of pomalidomide decreased T-cell senescence and increased T-cell activation in patients with Kaposi sarcoma, suggesting pomalidomide activity in Kaposi sarcoma stems in part from its immunomodulatory effects.

Cancer can affect all human organs and tissues and ranks as a prominent cause of death as well as an obstruction to increasing life expectancy. A notable breakthrough in oncology has been the inclusion of the immune system in fighting cancer, potentially prolonging life and providing long-term benefits. The concept of "immunotherapy" has been discussed from the 19th and early 20th centuries by Wilhelm Busch, William B. Coley and Paul Ehrlich. This involves distinct approaches, including vaccines, non-specific cytokines and adoptive cell therapies. However, despite the advances made in recent years, questions on how to select the best therapeutic options or how to select the best combinations to improve clinical outcomes are still relevant for scientists and clinicians. More than half of cancer patients receive radiotherapy (RT) as part of their treatment. With the advances in RT and immunotherapy approaches, it is reasonable to consider how to enhance immunotherapy with radiation and vice versa, and to investigate whether combinations of these therapies would be beneficial. In this chapter, we will discuss how the immune system responds to cancer cells and different cancer therapies with a focus on combination of RT and immunotherapy (radioimmunotherapy, RIT).

We have employed mathematical modeling techniques to construct a comprehensive framework for elucidating the intricate response mechanisms of the immune system, facilitating a deeper understanding of B-cell clonal deletion and somatic hypermutation. Our improved model introduces innovative mechanisms that shed light on positive and negative selection processes during T-cell and B-cell development. Notably, clonal deletion is attributed to the attenuated immune stimulation exerted by self-antigens with high binding affinities, rendering them less effective in eliciting subsequent B-cell maturation and differentiation. Secondly, our refined model places particular emphasis on the crucial role played by somatic hypermutation in modulating the immune system's functionality. Through extensive investigation, we have determined that somatic hypermutation not only expedites the production of highly specific antibodies pivotal in combating microbial infections but also serves as a regulatory mechanism to dampen autoimmunity and enhance self-tolerance within the organism. Lastly, our model advances the understanding of the implications of antibody in vivo evolution in the overall process of organismal aging. With the progression of time, the age-associated amplification of autoimmune activity becomes apparent. While somatic hypermutation effectively delays this process, mitigating the levels of autoimmune response, it falls short of reversing this trajectory entirely. In conclusion, our advanced mathematical model offers a comprehensive and scholarly approach to comprehend the intricacies of the immune system. By encompassing novel mechanisms for selection, emphasizing the functional role of somatic hypermutation, and illuminating the consequences of in vivo antibody evolution, our model expands the current understanding of immune responses and their implications in aging.

Tumour-associated macrophages (TAMs) often promote cancer progression through immunosuppression in the tumour microenvironment (TME). However, the signalling pathways crosstalk responsible for this mechanism remain unclear. The aim of our study was to investigate whether the interaction between TAMs and colorectal cancer cells could be down-regulated by nanoparticles (NPs) loaded with retinoic acid (RA) and coated with cholesterol (CHO), in combination with an anti-PD-L1 immune checkpoint inhibitor. Tumours were evaluated by qRT-PCR and immunohistochemistry from allographic tumour growth model. In addition, human tumours were evaluated by Tissue Microarray (TMA) and immunohistochemistry. Complementary analysis of epithelial-mesenchymal transition, cell migration, and macrophage polarisation were evaluated in vitro. We showed that the IL-10R/IL-10 axis is involved in overstimulation of the STAT3 pathway as well as downregulation of the NF-κB signalling pathway, which supports a loop of immunosuppressive cytokines that induces the M2-TAM phenotype. Furthermore, our combined findings suggest that the upregulation of STAT3/NF-κB pathways crosstalk mediated by immunosuppressive cytokines, such as IL-10/PD-L1/TGF-β, via M2-TAMs in the TME, leads to immunosuppression and epithelial-mesenchymal-transition of the colorectal cancer for stimulating Vimentin, CXCL12 and CD163 in the primary tumours. Importantly, NPs holding RA and coated with CHO in combination with anti-PD-L1 were more efficient in blocking this signalling pathway. These results contribute to our understanding of the immunological mechanisms, especially the re-educating of TAMs, and provide a novel management strategy for aggressive colorectal cancers using anti-PD-L1-conjugated nanocarriers.

The management of advanced renal cell carcinoma has advanced tremendously over the past decade, but most patients still do not receive durable clinical benefit from current therapies. Renal cellcarcinoma is an immunogenic tumor, historically with conventional cytokine therapies, such as interleukin-2 and interferon-α, and contemporarily with the introduction of immune checkpoint inhibitors. Now the central therapeutic strategy in renal cell carcinoma is combination therapies including immunecheckpoint inhibitors. In this Review, we look back on the historical changes in systemic therapy for advanced renal cell carcinoma, and focus on the latest developments and prospects in this field.

Apoptosis has been discovered as a mechanism of cell death. The purpose of this study is to identify the diagnostic signature factors related to bladder cancer (BLCA) through apoptosis related genes (ARGs). Clinicopathological parameters and transcriptomics data of 1,440 BLCA patients were obtained from 7 datasets (GSE13507, GSE31684, GSE32548, GSE32894, GSE48075, TCGA-BLCA, and IMvigor210). We first identified prognosis-related ARGs in BLCA and used them to construct two ARGs molecular subtypes by using consensus clustering algorithm. By using principal component analysis algorithms, a ARGscore was constructed to quantify the index of individualized patient. High ARGscore correlated with progressive malignancy and poor outcomes in BLCA patients. High ARGscore was associated with higher immune cell, higher estimate scores, higher stromal scores, higher immune scores, higher immune checkpoint, and lower tumor purity, which was consistent with the "immunity tidal model theory". Preclinically, BLCA immunotherapy cohorts confirmed patients with low ARGscore demonstrated significant therapeutic advantages and clinical benefits. These findings contribute to our understanding of ARGs and immunotherapy in BLCA. The ARGscore is a potentially useful tool to predict the prognosis and immunotherapy in BLCA.

In this review, we investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly cause myocarditis with severe myocardial damage induced by viral particles. A review of the major data published from 2020 to 2022 was performed by consulting the major databases alongside first-hand experiences that emerged from the cardiac biopsies and autopsy examinations of patients who died of SARS-CoV-2 infections. From this study, a significantly large amount of data suggests that the Dallas criteria were met in a residual percentage of patients, demonstrating that SARS-CoV-2 myocarditis was a rare clinical and pathological entity that occurred in a small percentage of subjects. All cases described here were highly selected and subjected to autopsies or endomyocardial biopsies (EMBs). The most important discovery, through the detection of the SARS-CoV-2 genome using the polymerase chain reaction, consisted in the presence of the viral genome in the lung tissue of most of the patients who died from COVID-19. However, the discovery of the SARS-CoV-2 viral genome was a rare event in cardiac tissue from autopsy findings of patients who died of myocarditis It is important to emphasize that myocardial inflammation alone, as promoted by macrophages and T cell infiltrations, can be observed in noninfectious deaths and COVID-19 cases, but the extent of each cause is varied, and in neither case have such findings been reported to support clinically relevant myocarditis. Therefore, in the different infected vs. non-infected samples examined, none of our findings provide a definitive histochemical assessment for the diagnosis of myocarditis in the majority of cases evaluated. We report evidence suggesting an extremely low frequency of viral myocarditis that has also been associated with unclear therapeutic implications. These two key factors strongly point towards the use of an endomyocardial biopsy to irrefutably reach a diagnosis of viral myocarditis in the context of COVID-19.

Approximately 10% of patients with colorectal cancer with submucosal invasion have lymph node metastasis. Pathological risk factors for lymph node metastasis have varying sensitivities and specificities. To predict the risk of lymph node metastasis, the identification of new risk factors is vital. Tumor-infiltrating T cells have been reported to improve the prognosis of many solid tumors. Therefore, the purpose of this study was to examine the relationship between lymph node metastasis and tumor-infiltrating T cells in patients with colorectal cancer with submucosal invasion. We examined CD8+ tumor-infiltrating T cells level as a risk factor for lymph node metastasis in patients with colorectal cancer with submucosal invasion. Using immunohistochemical staining, we identified CD8 + T cells in surgically resected specimens from 98 patients with SM-CRC. We showed that low CD8+ tumor-infiltrating T cells levels are positively correlated with lymph node metastasis. Furthermore, by combining the number of CD8+ tumor-infiltrating T cell and the number of CD103+ tumor-infiltrating T cells, the results showed a high positive predictive value for lymph node metastasis in cases with low numbers of both types of tumor-infiltrating T cells and a high negative predictive value in cases with high numbers of both types of tumor-infiltrating T cells.

Several mechanisms and cell types are involved in the regulation of the immune response. These include mostly regulatory T cells (Tregs), regulatory macrophages (Mregs), myeloid suppressor cells (MDSCs) and other regulatory cell types such as tolerogenic dendritic cells (tolDCs), regulatory B cells (Bregs), and mesenchymal stem cells (MSCs). These regulatory cells, known for their ability to suppress immune responses, can also suppress the anti-tumor immune response. The infiltration of many regulatory cells into tumor tissues is therefore associated with a poor prognosis. There is growing evidence that elimination of Tregs enhances anti-tumor immune responses. However, the systemic depletion of Treg cells can simultaneously cause deleterious autoimmunity. Furthermore, since regulatory cells are characterized by their high level of expression of immune checkpoints, it is also expected that immune checkpoint inhibitors perform part of their function by blocking these molecules and enhancing the immune response. This indicates that immunotherapy does not only act by activating specific effector T cells but can also directly or indirectly attenuate the suppressive activity of regulatory cells in tumor tissues. This review aims to draw together our current knowledge about the effect of immunotherapy on the various types of regulatory cells, and how these effects may be beneficial in the response to immunotherapy.

Recent studies have demonstrated that the uterus has its own microbiota. However, there is no consensus on endometrial microbiota composition, thus its role in the healthy uterine environment is still a frontier topic. Endometrial receptivity is key to embryo implantation, and in this specific context immunological tolerance against fetal antigens and the tightly regulated expression of inflammatory mediators are fundamental. According to recent evidence, endometrial microbiota may interact in a very dynamic way with the immune system during the peri-conceptional stage and later during pregnancy. For this reason, a condition of dysbiosis might lead to adverse pregnancy outcomes. The aim of this review is to summarize the evidence on the molecular mechanisms by which the endometrial microbiota may interact with the immune system. For this purpose, the link between dysbiosis and reproductive disorders, such as infertility, recurrent pregnancy loss (RPL), and preterm birth, will be discussed. In conclusion, the most recent findings from molecular analyses will be reported to illustrate and possibly overcome the intrinsic limitations of uterine microbiota detection (low endometrial biomass, high risk of contamination during sampling, and lack of standardization).

Heat shock protein 60 (HSP60) is an unique member of the heat shock protein family, being involved in parasite infections. To cope with harsh environments where parasites live, HSP60s are indispensable and involved in a variety of biological processes. HSP60s have relative low similarity among parasites, but their ATPase /Mg²⁺ active sites are highly conserved. The interactions of HSP60s with signaling pathway regulators in immune cells suggest a crucial role in immune responses, rendering them a potential therapeutic target. This paper reviews the current understandings of HSP60s in parasitic helminths in aspects of molecular characteristics, immunoregulatory responses and HSP60-based therapeutics.

The global COVID-19 pandemic began in March 2019, and given the number of casualties and adverse effects on the economy, society, and all aspects of the health system, efforts have been made to develop vaccines from the beginning of the pandemic. Numerous vaccines against COVID-19 infection have been developed in several technologies and have spread rapidly. There have been reported multiple complications of the COVID-19 vaccines as with other vaccines. A number of studies have reported multiple sclerosis (MS ) and neuromyelitis optica spectrum disorder (NMOSD) as complications of COVID-19 vaccines.

First, we found 954 studies from 4 databases (PubMed, Embase, Scopus, and Web of Science) from inception to March 1^st, 2022. Next, duplicate articles were eliminated, and 476 studies remained. Then 412 studies were removed according to inclusion and exclusion criteria. After obtaining the full text of 64 articles, 12 studies were selected finally.

The data were extracted from included studies in a table. Our data includes demographic data, comorbidities, vaccines information and side effects, NMOSD and MS symptoms, laboratory and cerebrospinal fluid (CSF) findings, magnetic resonance imaging (MRI) results, treatment, and outcome of all cases.

MS and NMOSD are two neuroinflammatory disorders that arise in the CNS. Cases of MS and NMOSD have been reported following COVID-19 vaccination. Nevertheless, more studies with more subjects are needed to assess any possible relationship between the COVID-19 vaccine and central nervous system demyelination.

Necroptosis, a type of programmed cell death, has recently been extensively studied as an important pathway regulating tumor development, metastasis, and immunity. However, the expression patterns of necroptosis-related genes (NRGs) in colorectal cancer (CRC) and their potential roles in the tumor microenvironment (TME) have not been elucidated.

We explored the expression patterns of NRGs in 1247 colorectal cancer samples from genetics and transcriptional perspective. Based on a consensus clustering algorithm, we identified NRG molecular subtypes and gene subtypes, respectively. Furthermore, we constructed a necroptosis-related signature for predicting overall survival time and verified the predictive ability of the model. Using the ESTIMATE, CIBERSORT, and ssGSEA algorithms, we assessed the association between the above subtypes, scores and immune infiltration.

Most NRGs were differentially expressed between CRC tissues and normal tissues. We found that distinct subtypes exhibited different NRGs expression, patients' prognosis, immune checkpoint gene expression, and immune infiltration characteristics. The scores calculated from the necroptosis-related signature can be used to classify patients into high-risk and low-risk groups, with the high-risk group corresponding to reduced immune cell infiltration and immune function, and a greater risk of immune dysfunction and immune escape.

Our comprehensive analysis of NRGs in CRC demonstrated their potential role in clinicopathological features, prognosis, and immune infiltration in the TME. These findings help us deepen our understanding of NRGs and the tumor microenvironment landscape, and lay a foundation for effectively assessing patient outcomes and promoting more effective immunotherapy.

The poor prognosis of head and neck cancer (HNC) is associated with metastasis within the lymph nodes (LNs). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN-negative or -positive tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision-making. Protein profiles are strictly associated with immune modulation across datasets, and this provides the basis for investigating immune markers associated with metastasis. The proteome of LN metastatic cells recapitulates the proteome of the primary tumor sites. Conversely, the LN microenvironment proteome highlights the candidate prognostic markers. By integrating prioritized peptide, protein, and transcript levels with machine learning models, we identify nodal metastasis signatures in blood and saliva. We present a proteomic characterization wiring multiple sites in HNC, thus providing a promising basis for understanding tumoral biology and identifying metastasis-associated signatures.

Surgical resection continues to be the mainstay treatment for solid cancers even though chemotherapy and immunotherapy have significantly improved patient overall survival and progression-free survival. Numerous studies have shown that surgery induces the dissemination of circulating tumor cells (CTCs) and that the resultant inflammatory response promotes occult tumor growth and the metastatic process by forming a supportive tumor microenvironment (TME). Surgery-induced platelet activation is one of the initial responses to a wound and the formation of fibrin clots can provide the scaffold for recruited inflammatory cells. Activated platelets can also shield CTCs to protect them from blood shear forces and promote CTCs evasion of immune destruction. Similarly, neutrophils are recruited to the fibrin clot and enhance cancer metastatic dissemination and progression by forming neutrophil extracellular traps (NETs). Activated macrophages are also recruited to surgical sites to facilitate the metastatic spread. More importantly, the body's response to surgical insult results in the recruitment and expansion of immunosuppressive cell populations (i.e. myeloid-derived suppressor cells and regulatory T cells) and in the suppression of natural killer (NK) cells that contribute to postoperative cancer recurrence and metastasis. In this review, we seek to provide an overview of the pro-tumorigenic mechanisms resulting from surgery's impact on these cells in the TME. Further understanding of these events will allow for the development of perioperative therapeutic strategies to prevent surgery-associated metastasis.