ImmunoTargets and Therapy最新文献

Purpose: The pathogenesis of T cell subsets in sepsis during the body's resistance to infection is currently unknown. We aimed to investigate the dynamics and molecular mechanisms of T cells during the development of sepsis.

Patients and methods: Perform single-cell data analysis on peripheral blood mononuclear cells (PBMCs) specimen samples from seven healthy controls, five early-stage sepsis patients, and four late sepsis patients, and the atlas were mapped and analyzed using reference mapping to identify the T cell subpopulations specific to early sepsis. Expression network upstream to investigate the changes of regulatory transcription factors and pathways by pySCENIC.

Results: Twenty-two CD4⁺ T-cell subpopulations and 10 CD8⁺ T-cell subpopulations were identified by mapping analysis. At the early stage of sepsis, we observed altered ratios of multiple immune cells in PBMCs. Three cell types CD4 Tn cells, CD8 (GZMK⁺ early Tem), and CD8 (ZNF683⁺CXCR6^- Tm) showed an upward trend (p < 0.05) in the early stages of sepsis compared to normal and returned to normal levels after two weeks. In addition, we found the presence of four sepsis-specific transcription factors (MXI1, CHD1, ARID5A, KLF9) in these three types of cells, which were validated in two external datasets. The differentially expressed genes in CD4 Tn cells, CD8 (GZMK⁺ early Tem), and CD8 (ZNF683⁺CXCR6^- Tm) cells between the healthy group and the early-stage sepsis group are commonly enriched in the allograft rejection pathway. In addition, it was found that CD8 cells exhibit a trend towards differentiation into CD8 Temra cells in sepsis.

Conclusion: We successfully depicted the dynamic changes of T cell subsets during sepsis onset and progression, which provides important clues for an in-depth understanding of T cells' function and regulatory mechanisms during sepsis pathogenesis.

Introduction: Chemotherapy combined with immune checkpoint inhibitors (ChIM) is used to treat advanced pancreatic ductal adenocarcinoma (PDAC). However, the efficacy of ChIM is similar to that of chemotherapy alone.

Methods: To assess potential factors affecting the effectiveness of ChIM, we analyzed the clinical data of 359 patients with PDAC who visited the hospital during June 2017 to December 2022.

Results: Surgical resection, diabetes, and ChIM were risk factors for pancreatic exocrine insufficiency (PEI). The adjusted odds ratio of ChIM was 2.63 (95% confidence interval (CI) 1.492-4.626) (P = 0.001). The incidence of PEI in the ChIM group (76.9%) was significantly higher than that of the chemotherapy group (60.2%) (P = 0.004). Survival analysis showed that ChIM did not improve the survival rate of patients with PDAC (hazard ratio (HR) 0.92, 0.707-1.197) (P = 0.534) in comparison with that of the chemotherapy group. However, in patients without PEI, those receiving ChIM showed a higher 1-year overall survival (OS) rate of 70.8% (two-sided, P = 0.045) and a median OS of 22.0 months (95% CI 11.5-32.5). Moreover, pancreatic enzyme replacement therapy significantly improved the OS of patients with PDAC (HR = 0.73, 95% CI = 0.561-0.956) (P = 0.022).

Conclusion: Immune checkpoint inhibitors (ICIs) increased the incidence of PEI in patients with PDAC. The OS was not different between patients receiving chemotherapy and ChIM due to irregular PERT treatment. The finding show that pancreatic enzyme replacement therapy may improve the response rate of patients with PDAC to ICIs.

Background: Ethiopians use Artemisia abyssinica and Lepidium sativum as immunity enhancers. However, there is no scientific validation conducted so far regarding this claim. The aim of this study was to investigate the in-vivo immunomodulatory activities of essential oils of A. abyssinica and L. sativum in mice.

Methods: The extraction was carried out using the earlier techniques. By hydro distilling fresh seeds and aerial portions of A. abyssinica and L. sativum, respectively, essential oils were obtained. Essential oils of both plants were tested at 100, 200 and 400 mg/kg. The rate of carbon clearance, humoral antibody titer, delayed type hypersensitivity response, spleen and thymus indices were evaluated in mice according to scientific protocols. The carbon clearance assay was determined using carbon ink. Sheep red blood cell was used as an antigen for other tests.

Results: Essential oils of A. abyssinica and L. sativum at 400 mg/kg significantly increased the rate of carbon clearance from the body of mice (p<0.05). The maximum carbon clearance rate was achieved for A. byssinica essential oil at 400 mg/kg. Both essential oils raised the level of HAT to SRBC in comparison to the vehicle and cyclophosphamide administered groups. The largest (84.668±1.951) mean secondary HAT to SRBC was generated by L. sativum essential oil at 400 mg/kg (p<0.001). A. abyssinica essential oil at 200 and 400 mg/kg significantly increased the level of thymus index compared to the model group (p<0.05 and 0.01 respectively). The levamisole group experienced the highest increase in thymus index (p<0.001). Essential oil of L. sativum at 400 mg/kg also increased the level of thymus index. The spleen index in mice was improved by the essential oils only at the highest dose levels (400 mg/kg).

Conclusion: It can be inferred that the essential oils of L. sativum and A. abyssinica have immunostimulant properties.

Background: The important roles of B7 homologous body 4 (B7-H4), B and T lymphocyte attenuator (BTLA) in patients with pulmonary tuberculosis (PTB) have been reported. This study aims to evaluate the association among B7-H4 and BTLA genes polymorphism, methylation and PTB susceptibility.

Methodology: Here, we assessed the possible relationship of 10 single nucleotide polymorphisms (SNPs) in B7-H4, BTLA genes with PTB susceptibility in a Chinese population (496 PTB patients and 502 controls) by SNPscan technique. Then, the B7-H4, BTLA genes methylation levels among 98 PTB patients and 97 controls were detected using MethylTarget technique.

Results: This study found no significant differences in allele and genotype frequencies of B7-H4 gene rs10754339, rs10801935, rs10923223, rs1937956, rs3738414, BTLA gene rs1982809, rs2971205, rs75368388, rs9288953 variants between PTB patients and controls. Haplotype analysis suggested that the lower frequencies of B7-H4 AATTG haplotype, BTLA GATT haplotype and the higher frequency of BTLA AGTC haplotype were found in PTB patients when compared with controls. We also found that the frequency of BTLA gene rs9288953 C allele was significantly increased in PTB patients with drug resistance. Moreover, the methylation levels of B7-H4 and BTLA genes in PTB patients were greater than that in controls, and rs10754339 variant in B7-H4 gene could affect its methylation level in PTB patients.

Conclusion: B7-H4, BTLA genes polymorphism might not affect PTB susceptibility, while the abnormal methylation levels of B7-H4, BTLA genes were associated with the genetic background of PTB.

Introduction: The BCL-2 inhibitor venetoclax has been widely used in the treatment of acute myeloid leukemia (AML); however, AML patients treated with venetoclax gradually develop resistance. The exportin-1 (XPO1) inhibitor selinexor can synergistically promote the antileukemia activity of venetoclax, but the mechanism remains unclear.

Methods and results: Annexin V/7-aminoactinomycin D assays were used to examine the effects of a combination of venetoclax and selinexor (VEN+SEL) on AML cell lines and primary AML cells. RNA sequencing and oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) determinations by a Seahorse XF analyzer were employed to investigate the molecular mechanism of the toxicity of the VEN+SEL combination to AML cells. The cytotoxicity of NK cell combined with VEN+SEL combination was assessed in vitro using flow cytometry. VEN+SEL enhanced the apoptosis of AML cells (KG-1A and THP-1) and primary AML samples in vitro. The ECAR and OCR results demonstrated that the VEN+SEL combination significantly inhibited glycolytic function. RNA sequencing of THP-1 cells demonstrated that DNA replication-related genes were downregulated after treatment with the VEN+SEL combination.

Conclusion: This study indicated that selinexor can synergistically enhance the antileukemia activity of venetoclax in AML cells in vitro by inhibiting glycolytic function and downregulating DNA replication-related genes. Based on our experimental data, combining selinexor with venetoclax is an appropriate advanced treatment option for AML patients.