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摘要： CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGFβtrap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., αPDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGFβtrap, IL15, or IL12 molecules fused to αPDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with αPDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with αPDL1 fused with TGFβtrap or IL15. Further, αPDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFNγ production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our αPDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.

关键词： kujigamberol   NFAT   T cells   interferon gamma   interleukin-2   interleukin-4   Fas ligand   eomesodermin  

摘要： Kujigamberol, a dinorlabdane compound isolated from Kuji amber, exerts multiple biological effects, including anti-allergic and anti-inflammatory activities. The present study demonstrated that kujigamberol inhibited cytokine production by T cells. In response to a phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM) stimulation, kujigamberol suppressed interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) mRNA expression in murine T-cell lymphoma BW5147 cells stably transfected with the T-box transcription factor eomesodermin. IL-4 and Fas ligand mRNA expression was also inhibited by kujigamberol. In the murine cytotoxic T-cell line CTLL-2, kujigamberol more strongly decreased IFN-gamma mRNA expression induced by IM alone than that induced by the combination of PMA and IM. A luciferase reporter assay showed that kujigamberol preferentially reduced nuclear factor of activated T cell (NFAT)-dependent transcription in human embryonic kidney 293T cells. Unlike the calcineurin inhibitor FK506, kujigamberol did not markedly affect NFATc2 protein levels in BW5147 cells but interfered with the binding of NFATc2 to the IFN-gamma and IL-2 promoters. These results indicate that kujigamberol inhibited IFN-gamma and IL-2 mRNA expression by preventing the binding of NFATc2 to their promoters;therefore, it has potential as an immunosuppressive agent.

关键词： eosinophilic esophagitis   interferon-gamma   interleukin-10   regulatory B cells  

摘要： Background: Eosinophilic Esophagitis (EoE) is a chronic food allergy that causes esophageal inflammation and fibrosis and manifests with symptoms of reflux, chest pain, swallowing difficulty, and food impactions. Though the prevalence of EoE is increasing by similar to 15% each year, our understanding of EoE immunopathology is limited. A noted feature of EoE is the presence of food-specific IgG4 antibodies in the circulation and esophageal tissue. Production of IgG4 is confined to IL-10+ B cells (Bregs) in other allergic diseases, suggesting Bregs may be present in EoE. Methods: We examined circulating Bregs in patients with EoE milk allergy. In parallel, we performed mechanistic investigations of the role of Bregs in a murine model of food-antigen-dependent EoE. Flow cytometry and histologic analyses were used to assess esophageal and draining lymph node immune cells, and in vitro assays were used to evaluate Breg functional capacity. Results: Breg frequency was reduced in both EoE milk allergic subjects and an EoE disease model. Murine Breg suppressive capacity was impaired during EoE-like inflammation. Inducible deletion of Breg-derived IL-10 worsened EoE-like inflammation, while adoptive transfer of IL-10 sufficient Bregs suppressed DC activation and improved esophageal eosinophilia. IFN gamma was sufficient to suppress Breg expansion and IL-10 production in vitro and contributed to Breg dysfunction and esophageal inflammation in vivo. Conclusion: Bregs play an immunoregulatory role during EoE by controlling esophageal eosinophilia but are functionally impaired due to IFN gamma-mediated signaling. These findings have important implications for understanding EoE's etiology and implementing future therapies that target IFN gamma.

关键词： kidney   mismatch   non-HLA   transplantation  

摘要： HLA-matching between donor (D) and recipient (R) is routinely performed in kidney allocation to optimize allograft survival but explains only a moderate variability of these outcomes. Recent findings suggest that donor-to-recipient mismatches outside the HLA region contribute to alloimmunity and graft loss, but the extent varies in different publications. We therefore conducted a systematic review of publications on this subject using a broad search string in our literature review in accordance with current guidelines for systematic reviews. The effect sizes were analyzed by a meta-analysis. A total of 1890 publications from 2019-25 within three different repositories (465 Medline, 1408 Embase, 17 Central) were systematically screened using the PICOTS (Population, Intervention, Comparator, Outcome, Time and Setting) system, which resulted in 12 eligible papers that met the inclusion criteria. Cohort studies that investigated the association of D-R non-HLA SNP mismatch and graft rejection/loss in renal transplant patients were included. We found that overall SNP mismatch between D-R pairs outside the HLA region was independently numerically associated with rejection hazard ratio (HR) 1.26 [95% confidence interval (CI) 0.97-1.65] and graft loss HR 1.35 (95% CI 0.86-2.12). Furthermore, loss of function mutation of the gene LIMS1 in the recipient who received a transplant organ with at least one functioning copy (collision genotype) was numerically associated with rejection HR 1.23 (95% CI 0.68-2.23) and graft loss HR 1.43 (95% CI 0.61-3.36). The exact quantification of the effect size of these mismatches varied by publication and needs further investigation. Based on these data, the strength of immunosuppression may be guided by the load of D-R mismatches in the future. 10.1093/ndt/gfaf073 Video Abstract Watch the video abstract of this contribution at https://***/ndt/pages/author_videos gfaf073Media1 6373014838112

关键词： Chemoresistance   Colorectal cancer   Inflammation   Nanocrystals   Xanthatin  

摘要： Poor water-solubility of emerging new chemotherapeutic drugs lead to low absorption and tissue bioavailability. Improved drug delivery has therefore recently been achieved through the versatile physico-chemical properties of nanocrystals (NCs) in targeted cancer therapies. Here, nanocrystalization was used with xanthatin, a not highly water-soluble natural sesquiterpene lactone compound that possesses anti-tumour properties and which was recently investigated for potential use in the treatment of cancer and autoimmune diseases. Given that tumour-promoting inflammation is a hallmark of colorectal cancer (CRC), and that epidemiological studies associated inflammatory biomarkers to CRC poor prognosis and therapy resistance, the anti-inflammatory properties of xanthatin NCs were assessed in 2D monolayers and in 3D spheroids of a human HT29 CRC cell model. The 3D spheroids being a model recapitulating a cancer stem cells and chemoresistant phenotype. HT29 2D monolayer cell response was first tested against four pro-inflammatory inducers including phorbol-12-myristate-13-acetate, tumour necrosis factor alpha (TNF alpha), transforming growth factor beta, and Concanavalin A. Of these inducers, HT29 cell response to TNF alpha resulted in the most elevated expression of cyclooxygenase (COX)-2 which was prevented by commercial xanthatin along with the phosphorylation of the extracellular signal-regulated kinase 1/2 and of IkappaB (I kappa B). Alteration of 3D spheroids formation and of the inflammatory/immunity transcriptomic signature was also found better altered by xanthatin NCs in comparison to commercial xanthatin and the isolated molecule. Collectively, our data indicate that xanthatin nanocrystallization did not alter the potential in vitro anti-inflammatory and anticancer properties of xanthatin against a 3D CRC chemoresistance cellular model. These properties make NCs a significant advancement in the field of cancer theranostics to improve patient outcomes.

摘要： OBJECTIVE:To investigate the role of senescent epidermal basal cells in cutaneous lupus erythematosus (CLE) pathogenesis using skin samples from patients with CLE and a mouse model of systemic lupus erythematosus (SLE). METHODS:Cellular senescence profiling utilized datasets from the NCBI Gene Expression Omnibus database and Accelerating Medicines Partnership® (AMP®) Phase 1-Metro. Gene array data from GSE184989 (CLE: n = 68, control: n = 4), single-cell RNA sequencing data from GSE186476 (CLE: n = 7, control: n = 14), and AMP® Phase 1-Metro (SLE: n = 17) were utilized. In vitro experiments further examined the expression of p21, type I interferon (IFN), human leukocyte antigen class I (HLA-I), and epidermal growth factor receptor (EGFR) signalling. Pharmacological clearance of senescent cells was performed using the senolytic drug fisetin in the SLE mouse model. RESULTS:p21-high senescent epidermal basal cells in patients with CLE exhibit high type I IFN expression. These cells enhance IFN signalling in surrounding normal epidermal basal cells, leading to increased HLA-I expression. In contrast, senescent epidermal cells upregulate EGFR signalling, which downregulates HLA-I expression, allowing them to evade immune surveillance. This heterogeneity of HLA-I expression promotes CD8-positive T-mediated toxicity against normal epidermal basal cells, resulting in their apoptosis. Pharmacological clearance of senescent epidermal basal cells improved SLE-like skin lesions. CONCLUSION:Senescent cells create a microenvironment that directs cytotoxic T-cell-mediated responses against normal epidermis in CLE, contributing to disease pathology. Targeting senescent cells and their signalling pathways may offer novel therapeutic strategies for CLE and SLE skin lesions.

关键词： Autoinflammatory disease   Canakinumab   IL-1   Investigator-initiated clinical trial   Schnitzler syndrome   AE   adverse events   ALP   alkaline phosphatase   CAPS   cryopyrin-associated periodic syndrome   CH   clonal hematopoiesis   CR   complete clinical response   CRP   C-reactive protein   DLQI   dermatology life quality index   DTW   dynamic time warping   IIT   investigator-initiated trial   NR   no clinical response   PCA   principal component analysis   PGA   physician global assessment   PR   partial clinical response   QoL   quality of life   SAA   serum amyloid A   SchS   Schnitzler syndrome   SF-36   36-item Short Form health survey   UMAP   uniform manifold approximation and projection   WBC   white blood cells  

摘要： Background Schnitzler syndrome (SchS) is a late-onset autoinflammatory disease characterized by urticarial rash and monoclonal gammopathy. SchS shares clinical features with cryopyrin-associated periodic syndrome, which is driven by gain-of-function mutations in NLRP3 , and while IL-1β-targeted therapies have shown efficacy, the underlying pathogenesis of SchS remains unclear. Methods During a multicenter, single-arm, open-label, investigator-initiated trial evaluating the efficacy and safety of canakinumab in five Japanese patients with SchS (named the SCan Study after SchS and Canakinumab), based on a similar study conducted in Germany, we measured 32 cytokines/chemokines and 11 complement-related factors in plasma and analyzed their correlations with changes in clinical symptoms during treatment. Furthermore, in two cases, single-cell RNA sequencing of peripheral blood and spatial transcriptomic analysis of lesional skin were performed to identify IL1B -expressing cells. Results The improvement in clinical symptoms and quality of life was maintained for 48 weeks following canakinumab treatment. Notably, these changes in clinical symptoms strongly correlated with WBC count, neutrophil count, CRP, and serum amyloid A levels, which were used as evaluation parameters in this study. In contrast, IL-1β and most other cytokines/chemokines exhibited distinct patterns and were not useful as markers of disease activity. IgM levels remained stable without an upward trend. Additionally, IL1B -expressing cells were predominantly neutrophils in both peripheral blood and lesional skin. Furthermore, neutrophil counts in peripheral blood decreased following canakinumab administration. Conclusions This study demonstrated that the primary source of IL1B- expressing cells in SchS is neutrophils. Moreover, canakinumab improves clinical symptoms by regulating neutrophil dynamics in peripheral blood.

摘要： Crystallization-induced asymmetric transformations can dramatically alter the product ratio from a reaction with inherently poor or undesired selectivity. Reported herein is a rare example of a dynamic crystallization-induced diastereoselective Strecker reaction which overrides the inherent substrate bias in the preparation of aryl-substituted tetrahydrofuran-derived non-natural amino acids. Discovery of a new non-hydrogenative auxiliary cleavage method enables application of the Strecker reaction to the large-scale syntheses of small molecule inhibitors of IL-17A.

关键词： chemokine   flagellin   lipopolysaccharide   rumen epithelium   short-chain fatty acids  

摘要： Objective:This study aimed to elucidate interleukin-1 beta (IL-1β) gene expression regulation and its function of defense mechanism in rumen epithelial cells of calves. Methods:Rumen tissues from six Holstein male calves were sampled at pre- (5 weeks of age, n = 3) and post-weaning (9 weeks of age, n = 3). IL-1β localization was analyzed using immunohistochemistry (IHC). Primary bovine rumen epithelial cells (BRECs) were treated with short-chain fatty acids (SCFAs), beta-hydroxybutyrate (BHBA), lactic acid, lipopolysaccharide (LPS), and flagellin, and IL-1β gene expression was analyzed by qRT-PCR. Additionally, bovine IL-1β-treated BRECs were assessed for cell proliferation, tight junction (TJ) protein expression, and chemokine mRNA expression. Results:IHC revealed IL-1β expression across all rumen epithelial layers. SCFAs, LPS, and flagellin significantly increased IL-1β mRNA expression (P < 0.05). Regarding the gene expression of rumen TJ proteins, CLDN4 and OCLN in suckling and weaned calves, as well as ZO-1 in weaned calves, showed significant decreases (P < 0.05), while CLDN1 in weaned calves showed a significant increase (P < 0.05) in IL-1β-treated BRECs. Regarding the gene expression of chemokines, the CCL2 expression significantly decreased (P < 0.05), while the CCL5 expression significantly increased (P < 0.05) in both suckling and weaned IL-1β treated BRECs. IL-1β treatment enhanced cell proliferation (P < 0.05). Conclusion:These results suggest that IL-1β induction by SCFAs, LPS, and flagellin, which increase in the rumen due to environmental changes, promotes cell proliferation in damaged rumen epithelium and contributes to its defense mechanism by upregulating CCL5 expression.