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AIMS: Interleukin (IL)-12p40 is a common subunit of the bioactive cytokines IL-12 and IL-23, and it also has its own intrinsic functional activity. However, its role in doxorubicin-induced chronic cardiomyopathy (DICCM) as well as the underlying mechanisms are still unknown. METHODS AND RESULTS: In this study, we used IL-12p40-knockout mice, IL-23p19-knockout mice, Rag1-knockout mice, a ferroptosis inhibitor, recombinant IL-12 (rIL-12), rIL-23, rIL-12p40, rIL-12p80, and anti-IL17A to investigate the effects of IL-12p40 on DICCM and elucidate the underlying mechanisms. We found that myocardial ferroptosis were increased in DICCM and that the inhibition of ferroptosis protected against DICCM. The expression of IL-12p40 was upregulated, and IL-12p40 was predominantly expressed by CD4+ T cells in the hearts of mice with DICCM. IL-12p40 knockout attenuated cardiac dysfunction, fibrosis and ferroptosis in DICCM, and similar results were observed in the context of CD4+ T cell IL-12p40 deficiency in Rag1-/- mice. Treatment with rIL-23, but not rIL-12, rIL-12p40 monomer or rIL-12p80, abolished the protective effects of IL-12p40 knockout. Moreover, rIL-23 treatment and IL-23p19 knockout exacerbated and ameliorated DICCM, respectively. IL-12p40 knockout might protect against DICCM by inhibiting Th17 differentiation and IL-17A production but not Th1, Th2 and Treg differentiation. Neutralizing IL-17A with an antibody also attenuated cardiac dysfunction, fibrosis and ferroptosis. The IL-12p40/Th17/IL-17A axis might promote cardiomyocyte ferroptosis by activating TNF receptor-associated factor 6 (TRAF6)/mitogen-activated protein kinase (MAPK)/P53 signaling in DICCM. CONCLUSIONS: Interleukin-12p40 deficiency protects against DICCM by inhibiting Th17 differentiation and the production of IL-17A, which plays critical roles in cardiomyocyte ferroptosis in DICCM via activating TRAF6/MAPK/P53 signaling. Our study may provide novel insights for the identification of therapeutic targets for treating DICCM in the clinic.

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This study aimed to determine the effect of ozone on the expression of Bax and Bcl-2 genes in dental pulp cells. Additionally, the programmed cell death protein 1, programmed death-ligand 1, and CD200 antigens were determined in lymphocytes to assess their surface expression. Dental pulp cells were cultured from extracted healthy third molars and characterized as dental pulp stromal cells. Gene expression of Bcl-2 and Bax was analyzed at 0 s, 6 s, and 12 s of ozone exposure using real-time PCR. Lymphocytes from dental pulp were subjected to ozone exposure for 12 s and PD-1, PD-L1, and CD200/CD200R expression was analyzed by flow cytometry. Upon exposure to ozone for 6 s, the Bcl-2 expression decreased significantly to -0.09, and at 12 s, it increased significantly to 0.3. Bax gene expression level increased significantly to 0.188 after 6 s exposure, and at 12 s, to 0.16. Lymphocytes exposed to ozone for 12 s showed minimal changes in PD-1, PD-L1, and CD200/CD200R expression levels, indicating that oxidative stress does not impact the signaling pathways regulating these molecules. The significant upregulation of Bcl-2 at 12 s highlights the cells' effort to protect themselves from prolonged oxidative stress, possibly tipping the balance toward cell survival and tissue repair. However, the absence of changes in PD-1 and PD-L1 expression on lymphocytes under oxidative stress suggests that these molecules are not sensitive to oxidative stress in this context.

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Antígenos CD , Apoptosis , Antígeno B7-H1 , Pulpa Dental , Ozono , Receptor de Muerte Celular Programada 1 , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Pulpa Dental/citología , Pulpa Dental/metabolismo , Apoptosis/efectos de los fármacos , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Antígenos CD/metabolismo , Antígenos CD/genética , Células Cultivadas , Estrés Oxidativo , Proyectos Piloto , Regulación de la Expresión Génica/efectos de los fármacos , Linfocitos/metabolismo , Linfocitos/inmunología , Linfocitos/efectos de los fármacos , Adulto Joven , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/genética , Adulto , Transducción de Señal/efectos de los fármacos

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Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations.

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T lymphocytes that infiltrate the tumor microenvironment (TME) often fail to function as effective anti-cancer agents. Within the TME, cell-to-cell inhibitory interactions play significant roles in dampening their anti-tumor activities. Recent studies have revealed that soluble factors released in the TME by immune and non-immune cells, as well as by tumor cells themselves, contribute to the exacerbation of T cell exhaustion. Our understanding of the cytokine landscape of the TME, their interrelationships, and their impact on cancer development is still at its early stages. In this review, we aim to shed light on Interleukin (IL) -6, IL-9, and IL-10, a small group of JAK/STAT signaling-dependent cytokines harboring T cell-suppressive effects in the TME and summarize their mechanisms of action. Additionally, we will explore how advancements in scientific research can help us overcoming the obstacles posed by cytokines that suppress T cells in tumors, with the ultimate objective of stimulating further investigations for the development of novel therapeutic strategies to counteract their tumor-promoting activities.

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Citocinas , Neoplasias , Microambiente Tumoral , Microambiente Tumoral/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Citocinas/metabolismo , Citocinas/inmunología , Animales , Linfocitos T/inmunología , Transducción de Señal , Medicina de Precisión , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo

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Bai et al investigate the predictive value of T lymphocyte proportion in Alzheimer's disease (AD) prognosis. Through a retrospective study involving 62 AD patients, they found that a decrease in T lymphocyte proportion correlated with a poorer prognosis, as indicated by higher modified Rankin scale scores. While the study highlights the potential of T lymphocyte proportion as a prognostic marker, it suggests the need for larger, multicenter studies to enhance generalizability and validity. Additionally, future research could use cognitive exams when evaluating prognosis and delve into immune mechanisms underlying AD progression. Despite limitations inherent in retrospective designs, Bai et al's work contributes to understanding the immune system's role in AD prognosis, paving the way for further exploration in this under-researched area.

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Introduction Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) have revolutionised treatment and improved outcomes in various malignancies. We aimed to evaluate CTLA-4 and PD-L1 immunoexpression in thyroid tumours and correlated them with clinicopathological parameters. Methods The study included 90 cases of thyroid malignancies comprising papillary thyroid carcinoma (PTC) (n = 64, 54.2%), follicular thyroid carcinoma (FTC) (n = 19, 16.1%), anaplastic thyroid carcinoma (ATC) (n = 3, 2.5%), and poorly differentiated carcinoma (n = 4, 3.4%), two cases (1.69%) of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) along with 26 cases (22%) of benign thyroid lesions. CTLA-4 (UMAB249) and PD-L1 (SP263) expression were assessed in all the cases of thyroid tumours. Results were compared with clinicopathologic parameters and overall survival. Results PD-L1 was positive in all three cases of anaplastic thyroid carcinoma (ATC), 33% (n = 21) cases of PTC, and 16% (n = 3) cases of FTC. PD-L1 positivity was significantly associated at tumour proportion score (TPS) ≥1% with lymphovascular invasion and age ≤40 years and at TPS ≥50% with tumour necrosis and N-stage. Immune proportion score (IPS) did not correlate with any clinicopathological parameters except for the N-stage. CTLA-4 was positive in six cases of PTC (1-5%); five showed lymph node involvement (p = 0.032). IPS was positive in 14 cases, and a significant association was seen with lymph node metastasis, lymphocytic infiltration, and lymphovascular invasion. Three cases of PTC showed co-expression for PD-L1 and CTLA-4 in tumour cells. No significant association was seen between PD-L1 expression and survival. Conclusion The current data suggest that PD-L1 is expressed in differentiated thyroid carcinoma, mainly PTC and ATC, indicating higher responsiveness to immunotherapy. A subset of PTC showed co-expression of PD-L1 and CTLA-4. These findings suggest the need for further investigation to utilise combinational immunotherapy, including anti-PD-L1 and anti-CTLA-4.

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PURPOSE: Assessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival. DESIGN: A retrospective cohort study METHODS: Data were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis. RESULTS: A cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2±11.9 years was included. The five most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < 0.0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; P = 0.0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < 0.0001). CONCLUSIONS: Ophthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.

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Luteolin, a commonly used traditional Chinese medicine, has been utilized for several decades in the treatment of hepatocellular carcinoma (HCC). Previous research has demonstrated its anti-tumour efficacy, but its underlying mechanism remains unclear. This study aimed to assess the therapeutic effects of luteolin in H22 tumour-bearing mice. luteolin effectively inhibited the growth of solid tumours in a well-established mouse model of HCC. High-throughput sequencing revealed that luteolin treatment could enhance T-cell activation, cell chemotaxis and cytokine production. In addition, luteolin helped sustain a high ratio of CD8+ T lymphocytes in the spleen, peripheral blood and tumour tissues. The effects of luteolin on the phenotypic and functional changes in tumour-infiltrating CD8+ T lymphocytes were also investigated. Luteolin restored the cytotoxicity of tumour-infiltrating CD8+ T lymphocytes in H22 tumour-bearing mice. The CD8+ T lymphocytes exhibited intensified phenotype activation and increased production of granzyme B, IFN-γ and TNF-α in serum. The combined administration of luteolin and the PD-1 inhibitor enhanced the anti-tumour effects in H22 tumour-bearing mice. Luteolin could exert an anti-tumour immune response by inducing CD8+ T lymphocyte infiltration and enhance the anti-tumour effects of the PD-1 inhibitor on H22 tumour-bearing mice.

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Linfocitos T CD8-positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Luteolina , Linfocitos Infiltrantes de Tumor , Luteolina/farmacología , Luteolina/uso terapéutico , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Ratones , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Línea Celular Tumoral , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Citocinas/metabolismo , Masculino , Granzimas/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ratones Endogámicos C57BL

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Objective: To evaluate the T-lymphocyte subset distribution and the diagnostic and prognosis value of double-negative T (DNT) cells in colorectal cancer (CRC). Methods: This retrospective study compared the T-lymphocyte subsets and DNT of 114 patients with CRC with those of 107 healthy controls (HC). The diagnostic potential of DNT and T-lymphocyte subsets was assessed using the receiver operating characteristic (ROC) curve, and prognostic values were evaluated using the Kaplan-Meier curve and the Cox regression model. Results: The percentages of CD8+ T cells and DNT cells, and value of carcinoembryonic antigen (CEA), were remarkably higher in patients with CRC than in those with HC, but the ratio of CD4+/CD8+ was decreased. Using ROC curve analysis, DNT cell percentage, CEA, and CD4+/CD8+ ratio all had good diagnostic efficacy, with areas under the curve (AUCs) of 0.865, 0.786 and 0.624, respectively. The combination of DNT cell percentage and CEA had an AUC of 0.905, which was significantly higher than that of any single biomarker (p < 0.05). In univariate analysis, the Tumor Node Metastasis (TNM) clinical stage, CD4+/CD8+ ratio, and DNT cell percentage were significantly associated with overall survival (OS) (p < 0.05). In multivariate analysis, TNM clinical staging (HR = 2.37, 95 % CI: 1.15-4.90), a decreased CD4+/CD8+ ratio (HR = 0.33, 95 % CI: 0.15-0.74), and an increased DNT cell percentage (HR = 2.29, 95 % CI: 1.11-4.73) were independent prognostic factors for CRC. Conclusion: The percentage of DNT cells may be useful as an evaluation index for CRC diagnosis and prognosis, which was even better when combined with serum CEA.

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Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.

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Síndrome de Liberación de Citoquinas , Citocinas , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Herpesvirus Humano 4/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Citocinas/inmunología , Citocinas/metabolismo , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/virología , Linfocitos B/inmunología , Linfocitos B/virología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/virología , Animales

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Enterovirus 71 (EV-71) has strong neurotropism, and it is the main pathogen causing severe hand, foot, and mouth disease (HFMD). In clinical observations, significant differences were observed in the severity and prognosis of HFMD among children who were also infected with EV-71. Genetic differences among individuals could be one of the important causes of differences in susceptibility to EV-71-induced HFMD. As P-selectin glycoprotein ligand-1 (PSGL-1) is an important receptor of EV-71, the correlation between single-nucleotide polymorphisms (SNPs) in PSGL-1 and the susceptibility to severe HFMD following EV-71 infection is worth studying. Given the role of PSGL-1 in immunity, the correlations between PSGL-1 SNPs and the immune status after EV-71 infection are also worth studying. Meanwhile, PSGL-1 variable number of tandem repeats (VNTR) represents a research hotspot in cardiovascular and cerebrovascular diseases, but PSGL-1 VNTR polymorphism has not been investigated in HFMD caused by EV-71 infection. In this study, specific gene fragments were amplified by polymerase chain reaction, and PSGL-1 VNTR sequences were genotyped using an automatic nucleic acid analyzer. The correlations of PSGL-1 VNTR polymorphism with the susceptibility to EV-71-associated severe HFMD and the post-infection immune status were analyzed. The PSGL-1 VNTR A allele was identified as a susceptible SNP for severe HFMD. The risk of severe HFMD was higher for AA + AB genotype carriers than for BB genotype carriers. The counts of peripheral blood lymphocyte subsets were lower in AA + AB genotype carries than in BB genotype carries. In conclusion, PSGL-1 VNTR polymorphism is associated with the susceptibility to EV-71-induced severe HFMD and the immune status after infection. PSGL-1 VNTR might play a certain role in the pathogenesis of severe cases.

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Enterovirus Humano A , Predisposición Genética a la Enfermedad , Enfermedad de Boca, Mano y Pie , Glicoproteínas de Membrana , Repeticiones de Minisatélite , Humanos , Enfermedad de Boca, Mano y Pie/genética , Enfermedad de Boca, Mano y Pie/inmunología , Enfermedad de Boca, Mano y Pie/virología , Glicoproteínas de Membrana/genética , Enterovirus Humano A/inmunología , Enterovirus Humano A/genética , Masculino , Femenino , Lactante , Repeticiones de Minisatélite/genética , Preescolar , Polimorfismo de Nucleótido Simple , Genotipo , Niño

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BACKGROUND: CD8+ T lymphocyte infiltration is closely associated with the prognosis and immunotherapy response of gastric cancer (GC). For now, the examination of CD8 infiltration levels relies on endoscopic biopsy, which is invasive and unsuitable for longitude assessment during anti-tumor therapy. PURPOSE: This work aims to develop and validate a noninvasive workflow based on contrast-enhanced CT (CECT) images to evaluate the CD8+ T-cell infiltration profiles of GC. METHODS: GC patients were retrospectively and consecutively enrolled and randomly assigned to the training (validation) or test cohort at a 7:3 ratio. All patients were binary classified into the CD8-high (infiltrated proportion ≥ 20%) or CD8-low group (infiltrated proportion < 20%) group. A total of 1170 radiomics features were extracted from each presurgical CECT series. After feature selection, fifteen radiomics features were transmitted to three independent machine-learning models for the computation of predictive radiological scores. Multilayer perceptron (MLP) was applied to merge the radiological scores with clinical factors. The predictive efficacy of the radiological scores and of the combined model was evaluated by receiver operating characteristic curve, calibration curve, and decision curve analysis in both the training and test cohorts. RESULTS: A total of 210 patients were enrolled in this study (mean age: 63.22 ± 8.74 years, 151 men), and were randomly assigned to the training set (n = 147) or the test set (n = 63). The merged radiological score was correlated with CD8 infiltration in both the training (p = 1.8e-10) and test cohorts (p = 0.00026). The combined model integrating the radiological scores and clinical features achieved an area under the curve (AUC) value of 0.916 (95% CI: 0.872-0.960) in the training set and 0.844 (95% CI: 0.742-0.946) in the test set for classifying CD8-high GCs. The model was well-calibrated and exhibited net benefit over "treat-all" and"treat-none" strategies in decision curve analysis. CONCLUSIONS: Artificial intelligent systems combining radiological features and clinical factors could accurately predict CD8 infiltration levels of GC, which may benefit personalized treatment of GC in the context of immunotherapy.

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Introduction: Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy. Methods: Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT. Results: CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature. Conclusion: These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT.

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Antígenos de Neoplasias , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Masculino , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Femenino , Transcriptoma , Anciano , Persona de Mediana Edad , Linfocitos T/inmunología , Linfocitos T/metabolismo , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología

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Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), also known as type II enteropathy-associated T-cell lymphoma, is a rare malignant lymphoma of the extranodal lymphoid tissue derived from interepithelial T lymphocytes. MEITL is a primary intestinal T-cell lymphoma with a challenging diagnosis and aggressive progression, and it can invade other extraintestinal sites. In this study, we report four patients diagnosed with MEITL. All patients presented with abdominal pain, and one patient was admitted because of acute intestinal perforation. Two patients presented with unformed defecation and diarrhea. All patients carried the immunophenotypes CD3, CD7, CD8, CD20, and CD56, and the Ki-67 index ranged 60% to 90%. Three cases were analyzed using next-generation sequencing. One case displayed possibly relevant alterations of CREBBP, NOTCH2, SETD2, and STAT5B, and another case exhibited definite alteration of NOTCH1, possibly relevant alterations of CCND1 and DNMT3A, and potentially relevant alterations of HISTH3B, IGLL5, KMT2C, and KRAS. Different chemotherapy regimens were used, but the prognosis was poor. Hence, we illustrated that because of its low incidence, challenging diagnosis, and difficult treatment, further therapeutic improvements are urgently warranted.

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Linfoma de Células T Asociado a Enteropatía , Humanos , Linfoma de Células T Asociado a Enteropatía/diagnóstico , Linfoma de Células T Asociado a Enteropatía/tratamiento farmacológico , Linfoma de Células T Asociado a Enteropatía/genética , Linfoma de Células T Asociado a Enteropatía/inmunología , Inmunofenotipificación , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/genética , Neoplasias Intestinales/inmunología , Pronóstico

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OBJECTIVE: To investigate the expression and significance of PD-1/PD-L1 in MDS blast cells, T lymphocyte cell subsets and Treg cells. METHODS: Eighty-eight MDS patients and 19 AML patients were collectd as the study subjects, and Iron deficiency anemia and healthy bone marrow donors were used as control group. The expression of PD-1/PD-L1 in MDS/AML blast cells, T lymphocyte cell subsets and Treg cells was detected by flow cytometry, and the expression level of Th1/Th2/Th17-related cytokines in peripheral serum was detected. RESULTS: The expression of PD-1/PD-L1 in blast cells, T lymphocyte cell subsets and Treg cells in low risk MDS group were lower than that in control group, medium and high risk MDS group and AML group（all P < 0.01）, and Th1/Th17 type cytokines were dominant. The expression of PD-1/PD-L1 in blast cells, T lymphocyte cell subsets and Treg cells of intermediate and high risk MDS group and AML group were higher than that of control group and low risk MDS group (all P < 0.01), and Th2 type and Treg type (IL-10、TGF-ß) cytokines were dominant. After treatment, the differences of PD-1/PD-L1 expression were not statisticatly significant in blast cells, T lymphocyte cell subsets and Treg cells between the MDS remission group and the control group (all P >0.05). The expression of PD-1/PD-L1 in blast cells, T lymphocyte cell subsets and Treg cells in MDS non-remission group were significantly higher than that in remission group and control group (all P < 0.01). CONCLUSION: The high expression of PD-1/PD-L1, dominance of Treg (IL-10、TGF-ß) and Th2-related cytokines and inhibition of effector T lymphocyte cells in patients with MDS is conducive to tumor cell proliferation and immune escape, which may promote the progression of MDS disease.

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Antígeno B7-H1 , Síndromes Mielodisplásicos , Receptor de Muerte Celular Programada 1 , Subgrupos de Linfocitos T , Linfocitos T Reguladores , Humanos , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Síndromes Mielodisplásicos/metabolismo , Leucemia Mieloide Aguda , Citocinas/metabolismo , Interleucina-10/metabolismo , Células Th17

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Although the host immune response is likely to be important for the prognosis of ENKTL, detailed information on the pre-treatment T lymphocyte subsets in ENKTL is lacking. To improve risk stratification for ENKTL patients, it is essential to look at the prognostic relevance of absolute CD3 + T cell counts (ACD3C), CD4 + T cell counts (ACD4C), and CD8 + T cell counts (ACD8C) for ENKTL. We retrospectively analyzed 46 ENKTL patients in the First Affiliated Hospital of Wenzhou Medical University between December 2016 and June 2022. Kaplan-Meier curves and log-rank tests were used to compare survival rates between groups according to the cut-off values of pre-treatment T lymphocyte subsets. Independent prognostic factors for survival were analyzed by Cox regression. ACD3C, ACD4C, and ACD8C were related to overall survival (OS) and progression-free survival (PFS) in ENKTL patients. Multivariate analyses identified pre-treatment ACD3C, ACD4C, and ACD8C as independent prognostic factors of survival, independent of the International Prognostic Index (IPI), prognostic index of natural killer lymphoma (PINK), and nomogram-revised risk index (NRI). The prognostic models incorporating pre-treatment T lymphocyte subsets and serum lactate dehydrogenase (LDH) could be used to stratify ENKTL patients into different prognostic groups with significantly different survivals. When superimposed on the IPI, PINK, or NRI categories, the ACD3C-LDH, ACD4C-LDH, and ACD8C-LDH models could better identify high-risk patients in the low-risk IPI, PINK, or NRI categories. In conclusion, the pre-treatment ACD3C, ACD4C, and ACD8C are effective prognostic survival indicators in ENKTL patients. When combined with LDH, they could better identify high-risk ENKTL patients.

RESUMEN

Optimized use of prophylactic or therapeutic donor lymphocyte infusions (DLI) is aimed at improving clinical outcomes in patients with malignant and non-malignant hematological diseases who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). Memory T-lymphocytes (CD45RA-/CD45RO+) play a crucial role in immune reconstitution post-HSCT. The infusion of memory T cells is proven to be safe and effective in improving outcomes due to the enhanced reconstitution of immunity and increased protection against viremia, without exacerbating graft-versus-host disease (GVHD) risks. Studies indicate their persistence and efficacy in combating viral pathogens, suggesting a viable therapeutic avenue for patients. Conversely, using virus-specific T cells for viremia control presents challenges, such as regulatory hurdles, cost, and production time compared to CD45RA-memory T lymphocytes. Additionally, the modulation of regulatory T cells (Tregs) for therapeutic use has become an important area of investigation in GVHD, playing a pivotal role in immune tolerance modulation, potentially mitigating GVHD and reducing pharmacological immunosuppression requirements. Finally, donor T cell-mediated graft-versus-leukemia immune responses hold promise in curbing relapse rates post-HSCT, providing a multifaceted approach to therapeutic intervention in high-risk disease scenarios. This comprehensive review underscores the multifaceted roles of T lymphocytes in HSCT outcomes and identifies avenues for further research and clinical application.

RESUMEN

BACKGROUND: Obesity is often associated with impaired immune responses, including enlarged spleen, increased inflammation, and impaired T-cell-mediated function, which may lead to increased susceptibility to infections. Bioactive compounds found in various fruits and vegetables (F&V) have been shown to have strong anti-inflammatory effects. However, few prospective studies have examined the effects of F&V on preventing obesity-associated dysregulation of immune and inflammatory responses. OBJECTIVE: The objective of this was to determine the impact of different levels of a mixture of F&V incorporated in a high-fat diet (HFD) on immune function changes in a diet-induced obesity animal model. METHODS: Six-wk-old male C57BL/6J mice were randomly assigned to 1 of 5 groups (n = 12/group): matched low-fat control (LF, 10% kcal fat) or HFD (45% kcal fat) supplemented with 0%, 5%, 10%, or 15% (wt/wt) freeze-dried powder of the most consumed F&V (human equivalent of 0, 3, 5-7, 8-9 servings/d, respectively) for 20 wk. Spleen weight was recorded, and the immunophenotype of splenocytes was evaluated by flow cytometry. Ex vivo splenic lymphocyte proliferation was assessed by thymidine incorporation and serum cytokines concentrations were measured by Meso Scale Discovery. RESULTS: Mice fed the HFD exhibited significantly higher spleen weight, decreased splenic CD8+ lymphocytes, suppressed T lymphocyte proliferation, and reduced serum IL-1ß and IFN-γ concentrations compared with those fed the LF diet. Feeding mice with the HFD supplemented with 10% or 15% F&V restored HFD-associated changes of these affected biomarkers compared with those fed HFD only. Furthermore, a significant correlation was found between immunologic markers and F&V level. CONCLUSIONS: These results suggest that increased consumption of F&V has beneficial effects in preventing HFD-associated dysregulation of immune function.

RESUMEN

Atopic dermatitis (AD) is a common allergic inflammatory skin condition marked by severe itching, skin lichenification, and chronic inflammation. AD results from a complex immune response, primarily driven by T lymphocytes and environmental triggers, leading to a disrupted epidermal barrier function. Traditional treatments, such as topical corticosteroids, have limitations due to long-term side effects, highlighting the need for safer alternatives. Here, we aimed to show that Agrimonia coreana extract (ACext) can be used in treating AD-related dermatologic symptoms. ACext could inhibit CRAC (Calcium Release-Activated Calcium) channel activity, reducing Orai1/CRAC currents and decreasing intracellular calcium signaling. This inhibition was further confirmed by the reduced IL-2 levels and T cell proliferation upon ACext treatment. In a mouse model of AD, ACext significantly ameliorates symptoms, improves histological parameters, and enhances skin barrier function, demonstrating its potential for treating AD.

Asunto(s)

Agrimonia , Dermatitis Atópica , Extractos Vegetales , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Ratones , Agrimonia/química , Modelos Animales de Enfermedad , Canales de Calcio Activados por la Liberación de Calcio/metabolismo , Canales de Calcio Activados por la Liberación de Calcio/antagonistas & inhibidores , Humanos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Señalización del Calcio/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/inmunología

RESUMEN

PURPOSE: By utilizing both protein and mRNA expression patterns, we can identify more detailed and diverse immune cells, providing insights into understanding the complex immune landscape in cancer ecosystems. MATERIALS AND METHODS: This study was performed by obtaining publicly available Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) data of peripheral blood mononuclear cells (PBMCs) from the Gene Expression Omnibus database. A total of 94674 total cells were analyzed, of which 32412 were T cells. There were 228 protein features and 16262 mRNA features in the data. The Seurat package was used for quality control and preprocessing, principal component analysis was performed, and Uniform Manifold Approximation and Projection was used to visualize the clusters. Protein and mRNA levels in the CITE-seq were analyzed. RESULTS: We observed that a subset of T cells in the clusters generated at the protein level divided better. By identifying mRNA markers that were highly correlated with the CD4 and CD8 proteins and cross-validating CD26 and CD99 markers using flow cytometry, we found that CD4+ and CD8+ T cells were better discriminated in PBMCs. Weighted Nearest Neighbor clustering results identified a previously unobserved T cell subset. CONCLUSION: In this study, we used CITE-seq data to confirm that protein expression patterns could be used to identify cells more precisely. These findings will improve our understanding of the heterogeneity of immune cells in the future and provide valuable insights into the complexity of the immune response in health and disease.

Asunto(s)

Transcriptoma , Humanos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Leucocitos Mononucleares/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Perfilación de la Expresión Génica/métodos , Linfocitos T/metabolismo , Linfocitos T/inmunología , Epítopos/genética , Epítopos/inmunología