IL-2 Signaling Research Articles

Understanding molecular differences in endocrine and exocrine pancreatic tissue in healthy and unhealthy metabolic states

Type II diabetes (T2D) is a metabolic disorder characterized by hyperglycemia largely due the development of insulin-resistance, and in some cases, due to insuffcient insulin secretion. The endocrine portion of the pancreas, the islets of Langerhans, is composed of a diverse population of cells (beta, alpha, delta) that play vital roles in glucose homeostasis. Intercellular signaling events that occur within this diverse cell population play an active role in T2D progression. Therefore, to properly understand the progression of T2D it is critical to understand the how both the cellular neighborhoods and cell-cell communications within the islet of Langerhans and the surrounding exocrine (non-Islet) tissue contribute to the development of T2D. As the pancreas is a heterogenous organ, techniques allowing for the identification of cellular subpopulations within the tissue, such as single-cell RNA sequencing (scRNAseq), have been critical to answering questions about the pathogenesis of T2D. However, these techniques provide no insight into the anatomical and spatial context of cells, and therefore lack the ability to determine the influence of cellular neighborhoods in T2D pathogenesis. To begin to fill the gap in our understanding of how cellular neighborhoods and cell-cell communication impacts the progression of T2D, we utilized cutting edge technology that allows for the identification of RNA and protein within tissue at cellular and subcellular level, the Nanostring CosMx Spatial Molecular Imager. In this study, we aimed to determine if the location of individual cells within the islet (exocrine adjacent versus endocrine adjacent) contributes to gene expression changes that direct disease progression. To answer this question, we collected 200 human donor pancreases and analyzed them for 1000 RNA targets using the CosMX Spatial Molecular Imager. Ig. We then performed an analysis of RNA expression of exocrine cells bordering the islets of Langerhans and endocrine cells surrounding pancreatic vasculature was compared between healthy, metabolically heathy obese (MHO), and obese T2D groups. Preliminary analysis of these data yield novel insights into the transcriptomic profile of metabolically unhealthy tissues that may play a role in the progression of T2D. In particular, we observed an upregulation of mRNA transcripts associated with pro-inflammatory IL-21 and IL-22 signaling in the alpha cells from MHO donor pancreases. Furthermore, this upregulation is primarily observed in alpha cells in close proximity to acinar cells. Overall, these data will help pave the way to addressing previously unanswered questions in the context of T2D pathogenesis and unexplored cell-cell interactions that occur between the endocrine and exocrine spaces of the pancreas. Funding: Saint Louis University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mapping the cellular landscape of the maternal-fetal interface in women with preterm birth and chronic chorioamnionitis

Abstract Preterm birth (PTB) affects over 15 million infants yearly. In up to 40% of late PTBs, placental examination reveals chronic chorioamnionitis (CCA), maternal mononuclear cell infiltration in the chorioamniotic membranes; yet, the cellular landscape remains fully unknown. Herein, we first used imaging mass cytometry (IMC) to map the phenotype and spatial distribution of immune cells at the maternal-fetal interface of women with PTB and CCA and non-CCA controls (n = 4 each). Cases exhibited a 5-fold increase in T cells, including effector memory CD4+ (p=0.02) and proliferative CD8+ T cells (p=0.04), and a 7-fold rise in CD163+CD206+ macrophages (p=0.05) compared to controls. NK cells were also present in both groups. Neighborhood analysis revealed that CD8+ T cells are in proximity to macrophages and CD4+Tbet+ T cells, and distanced from NK cells. Next, we performed spatial transcriptomics (STx) in each study group (n = 8 PTB with CCA, n = 7 PTB no CCA). STx highlighted diversity in several clusters of T cells, macrophages, and other immune cells found to be transcriptionally active in CCA. Gene ontology analysis indicated enrichment for CD8+ T cell activation, as well as IL-12 and IFNγ signaling in macrophages in CCA. Ongoing efforts are focused on validation and functional testing of such immune cells in order to unveil the complex interactions at the maternal-fetal interface in CCA, a placenta pathology associated with adverse outcomes in the mother and offspring.

Metabolic pathways in T cells are modulated by CCR7 and IL-7R to facilitate T cell motility.

Abstract T cells play an essential role in eliminating infections by migrating through tissues and interacting with antigen-presenting dendritic cells within lymph nodes, leading to activation. A continuous supply of energy is required for T cell movement to enable scanning of dendritic cells. Many studies have established that signaling through chemokine receptor CCR7 facilitates rapid movement, however, how CCR7 signaling induces T cell metabolism remains poorly understood. IL-7 signaling regulates glycolysis to promote T cell survival, but how signaling through the IL-7R affects T cell movement is unexplored. This study investigates the roles of CCR7 and IL-7R in metabolism to drive naïve T cell movement. Utilizing Seahorse analysis, we observe that CCL21 signaling to CCR7 has no effect on glycolysis, yet decreases cellular respiration. Conversely, IL-7 has no effect on respiration but promotes glycolysis. We then determined whether oxidative phosphorylation and glycolysis play a role in CCL21 and IL-7 driven T cell movement. We employ inhibitors of oxidative phosphorylation such as rotenone to examine the influence of different metabolic pathways on T cell mobility. Our findings provide new insights into the intersection of metabolism and motility, suggesting potential differential mechanisms of ATP production that drive interactions.

Opposing roles of SWI/SNF chromatin remodeling complex BAF and PBAF in Effector Differentiation during Chronic Viral Infection

Abstract During chronic viral infection, CD4+ T cells help in the form of IL-21 is critical for the development of highly cytolytic effector CD8+ T cells. However, the exact signaling pathways from IL-21 that regulate CD8+ T cell function remain unclear. The current dogma states that IL-21 predominantly signals through STAT3, to generate effector CD8+ T cells during chronic viral infection. Here, we reveal a novel mechanism of IL-21 signaling via STAT4 for effector CD8+ T cell development following chronic LCMV infection. Furthermore, STAT4-mediated effector differentiation is epigenetically regulated by BAF, a SWI/SNF chromatin remodeling complex. In the absence of either STAT4 or BAF, virus specific CD8+ T cells fail to differentiate into highly cytolytic effector CD8+ T cells capable of controlling viral infection. The effector differentiation phenotype is balanced by PBAF, another component of the SWI/SNF complex, which promotes CD8+ T cell exhaustion during chronic LCMV infection. Conditional knockout of PBAF from CD8+ T cells impairs the development of T cell exhaustion, resulting in immunopathology and mortality of chronic LCMV-infected mice. Interestingly, this phenotype is dependent on the STAT4 and BAF-mediated transcriptional and chromatin changes. Overall, our findings underscore the delicate balance between effector and exhaustion pathways, governed by BAF and PBAF complex, to dictate the outcomes of immunopathology during chronic viral infections.

Function of tissue-resident helper T cells in chronic lung sequelae following viral pneumonia

Abstract Respiratory viral infections such as influenza and SARS-CoV-2 can lead to the development of chronic lung disease and impaired lung function long-term after the recovery from acute morbidity. However, the mechanisms underlying the development of chronic diseases post-acute respiratory viral infection are largely elusive. Using a model of age-related development of chronic lung disease after acute influenza infection, we found that a population of lung resident PD1HiCD4+ T helper cells (TRH), which exhibit characteristics of both follicular helper T cells and resident memory cells, was greatly increased after primary influenza pneumonia. Furthermore, TRH cells were located near the dysplastic/inflammatory lung parenchyma after the resolution of primary viral pneumonia. Strikingly, genetic ablation of TRH or the blockade of TRH-derived IL-21 signaling diminished chronic lung pathology and improved lung function following viral pneumonia in aged animals. Moreover, TRH cell presence was associated with worse lung function and increased lung pathology in COVID-19 convalescents. Our data suggest that exuberant TRH responses contribute to the development of chronic lung sequelae following viral pneumonia. Additionally, our findings may pave the way to develop novel preventive and/or therapeutic options treating chronic lung diseases following acute viral pneumonia including long COVID.

Abstract 132: Immunosenescence-related Biomarkers And Potential Therapeutic Targets For Coronary Artery Disease Identified Via Plasma Proteome And Immune Cell Traits

There is a pressing need to identify novel biomarkers and therapeutic targets to address the epidemiological burden of coronary artery disease (CAD). Mendelian Randomization analysis (MR) leverages Genome-Wide Association Study (GWAS) data to infer the causal mechanism underlying the phenotype of interest. The proteome is the central mediator of the etiology and pathophysiology of multifactorial diseases such as CAD. Here, we screened for potential biomarkers and therapeutic targets for CAD through MR by using genetically predicted levels of plasma proteome followed by immune cell traits and transcriptomic analysis. The main workflow of our study is outlined in Figure 1. Briefly, MR analysis was performed with protein quantitative trait loci (pQTL) and meta-analysis of four independent GWASs. Sensitivity analysis was performed to ensure the robustness of identified proteins. Pathway Enrichment analysis on whole-blood transcriptome was performed with GSEA. Secondary MR explored the causal effect of 731 immune cell traits on CAD risk. In total, 11 overlapping candidate proteins (P<0.05, OR>1.0) were identified from the plasma proteome meta-analysis, including LPA, PLA2G7, and PCSK9, substantiating the validity of our MR analysis. Functional annotation of candidate proteins identified LCAT and CA11 as promising therapeutic targets and biomarkers. LCAT suppression is protective against atherosclerosis in mice models, while the functional significance of CA11 remains to be elucidated. Transcriptomic analysis shows enrichment in IL-2 signaling pathways reflective of the exhaustion of CD28 on cytotoxic T cells identified via secondary MR using immune-cell traits. Together, these results are indicative of immunosenescence as a risk factor for CAD. Overall, our results revealed that an altered immune landscape increased the risk for CAD and unraveled an encouraging avenue for early diagnosis and treatment of CAD.

Resistance-Exercise-Induced Circulating Factors on Damaged Skeletal Muscle Tissue Proteome in Young Untrained Men

Recovery from muscle damage is tightly orchestrated by multiple physiological processes that can be altered by circulating factors (e.g., cytokines, growth factors) and intracellular signaling pathways (e.g., autophagy). Our previous studies have demonstrated that resistance exercise (RE)-induced circulating factors alter the expression of intramuscular cytokine mRNA and autophagic and myogenic markers in exercise-induced skeletal muscle damage (EIMD). However, the global effects of these circulating factors on damaged muscle are largely understudied. Purpose: To identify global changes in the proteome and functional pathways in skeletal muscle when EIMD is followed by an upper body RE-induced circulating milieu. Hypothesis: RE-induced circulating factors alter protein expression profile in damaged muscle. Methods: Vastus lateralis samples from 3 men included in the parent study were utilized for this report. Untrained men (age: 23 ± 5yr; height: 181.6 ± 5.9cm; weight: 86.0 ± 15.8kg) completed 2 identical bouts of maximal unilateral eccentric knee extensions for 8 sets of 10 repetitions, which were immediately followed by either heavy upper body RE to induce changes in circulating factors (EX) or 20 min seated rest (CON). Muscle samples from the damaged leg at 24h were used to compare between conditions. The total number of proteins was measured using LC-MS/MS. Bioinformatic analyses were performed via Qiagen Ingenuity Pathway Analysis software. For identifying enriched biological processes and functions, proteins had to have at least 1.0-fold differential expression with an FDR-adjusted significance level < 0.05. Z scores were calculated to predict changes in biological functions. Results: A total of 900 proteins were identified. For EX, 79 proteins were downregulated, and 15 were upregulated compared to CON at 24h. Pathway analyses demonstrated that for EX, there was decreased activation in acute phase response signaling, liver X receptor/retinoid X receptor activation, nitric oxide production and reactive oxygen species in macrophages, and neutrophil extracellular trap signaling pathways compared to CON. In addition, for EX, there was an increase in macrophage IL-12 signaling and production than CON. Conclusion: RE-induced changes in circulating factors modulated pathways associated with the immune response and cytokine signaling in untrained men. Given that immune response is critical for recovery from muscle damage, these results highlight the potential role of RE-induced circulating factors (e.g., hormones, growth factors, etc.) which could play a role in mediating muscle recovery. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

IL10 signal of lung interstitial macrophages prevents progressive lung fibrosis by suppressing commensal dysbiosis

IL10 signal of lung interstitial macrophages prevents progressive lung fibrosis by suppressing commensal dysbiosis

IL-10 promotes mast cell homeostasis and differentiation towards a mucosal mast cell phenotype

Abstract We recently demonstrated an unexpected role for IL-10 in driving mast cell (MC) activation and proliferation. IL-10 stimulation significantly enhanced IgE-mediated MC activation, upregulated FceRI expression, and promoted MC-mediated food allergy. Surprisingly, IL-10 also amplified cytokine production in un-activated MCs and enhanced their proliferation and survival, suggesting a role for IL-10 in MC homeostasis. Herein, we demonstrate that IL-10 can significantly expand MC proliferation and activity during homeostatic conditions. Treatment with IL-10 enhanced the proliferation and survival of both IL-3 and IL-3+SCF cultured bone marrow-derived MCs (BMMCs). This corresponded with a dramatic increase in cytokine production in IL-10-treated cells, along with upregulation of FceRI expression. While SCF was dispensable for the increased FceRI, it significantly enhanced cytokine production compared to cells cultured in IL-3 alone. Further analysis revealed a distinctive mucosal MC phenotype in IL-10-treated cells, characterized by beta7-integrin expression and enhanced secretion of murine MC protease-1. Lastly, autocrine IL-10 also supported MC expansion and function, as blocking IL-10 signaling attenuated MC expansion, inducing apoptosis, and decreasing cytokine production. Taken together, these data suggest an important role for IL-10 in maintaining MC responses during physiological conditions.

Construction and evaluation of a metabolic correlation diagnostic model for diabetes based on machine learning algorithms.

Diabetes mellitus (DM) is a prevalent chronic disease marked by significant metabolic dysfunctions. Understanding its molecular mechanisms is vital for early diagnosis and treatment strategies. We used datasets GSE7014, GSE25724, and GSE156248 from the GEO database to build a diagnostic model for DM using Random Forest (RF) and LASSO regression models. GSE20966 served as a validation cohort. DM patients were classified into two subtypes for functional enrichment analysis. Expression levels of key diagnostic genes were validated using quantitative real-time PCR (qRT-PCR) on Peripheral Blood Mononuclear Cells (PBMCs) from DM patients and healthy controls, focusing on CXCL12 and PPP1R12B with GAPDH as the internal control. After de-batching the datasets, we identified 131 differentially expressed genes (DEGs) between DM and control groups, with 70 up-regulated and 61 down-regulated. Enrichment analysis revealed significant down-regulation in the IL-12 signaling pathway, JAK signaling post-IL-12 stimulation, and the ferroptosis pathway in DM. Five genes (CXCL12, MXRA5, UCHL1, PPP1R12B, and C7) were identified as having diagnostic value. The diagnostic model showed high accuracy in both the training and validation cohorts. The gene set also enabled the subclassification of DM patients into groups with distinct functional traits. qRT-PCR results confirmed the bioinformatics findings, particularly the up-regulation of CXCL12 and PPP1R12B in DM patients. Our study pinpointed seven energy metabolism-related genes differentially expressed in DM and controls, with five holding diagnostic value. Our model accurately diagnosed DM and facilitated patient subclassification, offering new insights into DM pathogenesis.

Short-Term Dietary Restriction Potentiates an Anti-Inflammatory Circulating Mucosal-Associated Invariant T-Cell Response.

Short-term protein-calorie dietary restriction (StDR) is a promising preoperative strategy for modulating postoperative inflammation. We have previously shown marked gut microbial activity during StDR, but relationships between StDR, the gut microbiome, and systemic immunity remain poorly understood. Mucosal-associated invariant T-cells (MAITs) are enriched on mucosal surfaces and in circulation, bridge innate and adaptive immunity, are sensitive to gut microbial changes, and may mediate systemic responses to StDR. Herein, we characterized the MAIT transcriptomic response to StDR using single-cell RNA sequencing of human PBMCs and evaluated gut microbial species-level changes through sequencing of stool samples. Healthy volunteers underwent 4 days of DR during which blood and stool samples were collected before, during, and after DR. MAITs composed 2.4% of PBMCs. More MAIT genes were differentially downregulated during DR, particularly genes associated with MAIT activation (CD69), regulation of pro-inflammatory signaling (IL1, IL6, IL10, TNFα), and T-cell co-stimulation (CD40/CD40L, CD28), whereas genes associated with anti-inflammatory IL10 signaling were upregulated. Stool analysis showed a decreased abundance of multiple MAIT-stimulating Bacteroides species during DR. The analyses suggest that StDR potentiates an anti-inflammatory MAIT immunophenotype through modulation of TCR-dependent signaling, potentially secondary to gut microbial species-level changes.

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy.

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.

IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rβγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

Loading-Dose Dupilumab May Function as a Prophylactic Agent for Food-Induced Anaphylaxis: A Case and Review of the Literature

Recent advances in targeted therapy using monoclonal antibodies have revolutionized care in many fields, and dupilumab for the treatment of moderate-severe atopic dermatitis is no exception. While on a trial of loading dose dupilumab, a 25-year-old white male with a past medical history significant for anaphylaxis after ingesting peanuts and tree nuts did not experience anaphylaxis after accidentally consuming almonds. Similarly to anti-IgE, the large-scale inhibition of IL-4 and IL-13 signaling to various immune cells involved with type II hypersensitivity reactions using loading dose dupilumab may have played a role in preventing anaphylaxis in this patient. The role of loading dose dupilumab as a potential prophylactic agent against food-induced anaphylaxis could be explored cautiously as a novel way to reduce both morbidity and mortality in patients with these allergies.

Abstract CT208: High tumor monocyte content predicts long-term survival for patients with operable oesophageal cancer treated with neoadjuvant immunochemotherapy in the LUD2015-005 trial

Abstract Background: Combined immune checkpoint inhibitors (ICI) with chemotherapy in advanced oesophageal cancer (OC) has shown survival benefit in phase III studies, resulting in ICI’s recent approval to treat advanced OC. The role of ICI in peri-operative OC is debated, and large clinical studies are ongoing. Patients’ response to immunochemotherapy is highly variable and it is unclear what underlies this heterogeneity. To address this challenge, 38 advanced and 35 operable OC patients were enrolled to receive ICI in the LUD2015-005 trial (NCT02735239). Methods: We investigated the clinical and biological effects of adding the anti-PD-L1 ICI durvalumab to peri-operative chemotherapy or chemoradiotherapy (CRT) in a phase II multicentre study (LUD2015-005 trial). Operable OC patients received ICI for four weeks, followed by combination treatment with ICI + chemotherapy (oxaliplatin and capecitabine or fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT)), or ICI + CRT (CROSS regimen). Patients could also receive ICI for up to 6 months after surgery. Tissue samples were collected at baseline, after four weeks ICI-only, and on the day of surgery. Further to assessing synergy of ICI with standard peri-operative treatment for OC, our trial design enables an in-depth analysis of molecular features of response, and to dissect the impact of ICI alone on the tumor microenvironment. Single cell and bulk transcriptomic data were generated and used to perform RNA deconvolution to estimate tumor cell composition. Results: The treatment was well-tolerated and two-year survival was 80% and 73.3% with ICI + chemotherapy and ICI + CRT, respectively. Survival was superior to that of propensity score matched patients receiving standard of care (p = 0.047). Tumor cell composition analysis revealed that neither total T-cell numbers nor a specific T-cell functional phenotype was associated with outcome, but high tumor monocyte content (TMC) at baseline was highly predictive of overall survival (p = 0.003). Moreover, a 13-gene core monocyte gene signature was sufficient to predict overall survival (p = 0.022) and major pathological response (mPR, Mandard 1-2, p = 0.009). Patients with mPR at resection showed enrichment of interferon and IL15 signalling at the four-week ICI-only timepoint (p < 0.001). Single cell trajectory interference combined with immune response enrichment analysis also show that high interferon and IL15 signalling drive monocytes to differentiate into M1 macrophages and dendritic cells. Conclusion: Similar to our previous finding in immunochemotherapy treated advanced OC patients (Carroll et al. Cancer Cell 2023), TMC is a highly predictive biomarker of long-term survival for operable OC patients treated with neoadjuvant immunochemotherapy, highlighting the importance of tumor monocytes and their differentiation potential in OC patients’ response to ICI. Citation Format: Hannah S. Fuchs, Sabrina A. James, Thomas M. Carroll, Phil F. Xie, Joseph A. Chadwick, Duncan Parkes, Simon R. Lord, Lucinda Griffiths, Tim Underwood, Ioannis Karydis, Russell T. Petty, Benjamin Schuster-Böckler, Richard P. Owen, Mark R. Middleton, Xin Lu. High tumor monocyte content predicts long-term survival for patients with operable oesophageal cancer treated with neoadjuvant immunochemotherapy in the LUD2015-005 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT208.

A study of scarless wound healing through programmed inflammation, proliferation and maturation using a redox balancing nanogel.

In the study, we have shown the efficacy of an indigenously developed redox balancing chitosan gel with impregnated citrate capped Mn3O4 nanoparticles (nanogel). Application of the nanogel on a wound of preclinical mice model shows role of various signaling molecules and growth factors, and involvement of reactive oxygen species (ROS) at every stage, namely hemostasis, inflammation, and proliferation leading to complete maturation for the scarless wound healing. While in vitro characterization of nanogel using SEM, EDAX, and optical spectroscopy reveals pH regulated redox buffering capacity, in vivo preclinical studies on Swiss albino involving IL-12, IFN-γ, and α-SMA signaling molecules and detailed histopathological investigation and angiogenesis on every stage elucidate role of redox buffering for the complete wound healing process.

CIRP increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TLR4-IL-2 signaling in the late phase of sepsis

BackgroundT helper (Th) cell imbalances have been associated with the pathophysiology of sepsis, including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Cold-inducible RNA-binding protein (CIRP), a novel damage-associated molecular pattern (DAMP) was reported that could induce T cell activation, and skew CD4+ T cells towards a Th1 profile. However, the effect and underlying mechanisms of CIRP on Th17/Treg differentiation in sepsis still remains unknown. MethodsA prospective exploratory study including patients with sepsis was conducted. Blood samples were collected from patients on days 0, 3 and 7 on admission. The serum CIRP and peripheral blood Treg/Th17 percentage was determined by ELISA and flow cytometry. CD4+ T cells from the spleen and lymph nodes of mice with experimental sepsis were collected after treatment with normal saline (NS), recombinant murine CIRP (rmCIRP) and C23 (an antagonist for CIRP-TLR4) at late stage of sepsis. RNA-seq was conducted to reveal the pivotal molecular mechanism of CIRP on Treg/Th17 differentiation. Naïve CD4+ T cell was isolated from the Tlr4 null and wildtype mice in the presence or absence rmCIRP and C23 to confirmed above findings. ResultsA total of 19 patients with sepsis finally completed the study. Serum CIRP levels remained high in the majority of patients up to 1 week after admittance was closely associated with high Treg/Th17 ratio of peripheral blood and poor outcome. A univariate logistic analysis demonstrated that higher CIRP concentration at Day 7 is an independent risk factor for Treg/Th17 ratio increasing. CIRP promotes Treg development and suppresses Th17 differentiation was found both in vivo and in vitro. Pretreated with C23 not only alleviated the majority of negative effect of CIRP on Th17 differentiation, but also inhibited Treg differentiation, to some extent. Tlr4 deficiency could abolish almost all downstream effects of rmCIRP. Furthermore, IL-2 is proved a key downstream molecules of the effect CIRP, which also could amplify the activated CD4+ T lymphocytes. ConclusionsPersistent high circulating CIRP level may lead to Treg/Th17 ratio elevated through TLR4 and subsequent active IL-2 signaling which contribute to immunosuppression during late phases of sepsis.

Efficacy and Safety of Dupilumab in the Treatment of Hand Eczema: A Retrospective Study.

Background: Hand eczema (HE) is a prevalent chronic condition that exerts a substantial and enduring adverse effect on quality of life (QoL) and imposes an economic burden on society. Managing HE poses challenges due to the limited effectiveness and potential adverse effects associated with many currently available topical and systemic treatments. Methods: This article examines twenty-one patients affected by HE treated with dupilumab, a fully human monoclonal antibody targeting interleukin IL-4 and IL-13 signaling. This involves a retrospective descriptive statistical analysis. Results: At week 6, HECSI-75 was achieved by 12 patients (57.9%). The proportion of patients meeting the HECSI-75 criteria steadily increased over the observation weeks, reaching 90% at week 16 and 100% at week 104. Furthermore, HECSI-90 and HECSI-100 were achieved by 75% and 60% of patients at week 16 and by 100% and 85% of patients at week 68, respectively. All patients who reached week 104 maintained complete disease remission according to HECSI 100. Conclusions: In all patients, dupilumab was shown to be an effective drug in achieving disease clearance, as indicated by all the parameters considered at each evaluation point (Week 6, Week 16, Week 32, Week 52, Week 68, Week 84, and Week 104), in comparison to the initial baseline.

Real-Life Study of Patient Preference for Dupilumab or Revision Surgery for Recurrent Chronic Rhinosinusitis with Nasal Polyps.

(1) Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a high rate of recurrence in patients, despite therapy with local corticosteroids and functional endoscopic sinus surgery. Dupilumab, a recombinant monoclonal human IgG4 antibody directed against the IL-4 receptor α that inhibits both IL-4 and IL-13 signal transduction, is available for symptomatic therapy. Patient preference between repeated surgery and injection therapy with Dupilumab is not known. (2) Methods: Patients who had experienced at least one surgical intervention for nasal polyps and were treated with Dupilumab for at least 3 months completed a retrospective patient questionnaire. (3) Results: In a cohort of 75 previously operated CRSwNP patients, 91.5% preferred therapy with Dupilumab to repeated surgery for nasal polyps. Preference for Dupilumab in the subgroups of patients with concomitant Non-steroidal Anti-inflammatory Drugs Exacerbated Respiratory Disease (N-ERD) (n = 32), patients with concomitant asthma (n = 25), and patients without concomitant disease (n = 18) was 100%, 96%, and 72%, respectively. (4) Conclusions: Patient preference for Dupilumab over repeat surgery is strongest in previously operated CRSwNP patients with concomitant asthma or N-ERD, but remains very high in patients without concomitant disease.