OBJECTIVES: To investigate the characteristics of immune cell infiltration in tumor samples from Chinese patients with clear cell renal cell carcinoma (ccRCC) and the correlation of immune cell infiltration with tumor stage and response to immunotherapy. METHODS: Tumor samples and clinicopathological data were collected from 154 ccRCC patients treated in Nanfang Hospital, Southern Medical University from October, 2020 to October, 2023. The immune cell types infiltrating the tumor tissues were identified using immunohistochemistry and immunofluorescence staining, and their correlations with the patients' clinicopathological characteristics were analyzed. Patient-derived tumor tissue fragment models (PDTF) models, constructed using tumor tissues from 22 patients, were treated with PD-1 monoclonal antibody, and T cell activation was detected using flow cytometry to assess the patients' responses to immunotherapy. RESULTS: In Chinese ccRCC patients included in this study, CD8⁺ T cells, CD4⁺ T cells, and CD3⁺ T cells were the most abundant in the tumor tissues. Higher infiltration levels of CD3⁺ T cells (P=0.004), PD-1⁺ T cells (P=0.020), CD68⁺ T cells (P=0.049), CD79⁺ T cells (P=0.049), and Tryptase⁺ cells (P=0.049) were all positively correlated with a larger tumor size (≥5 cm). A higher infiltration level of CD4⁺ T cells was associated with a lower tumor stage. Patients with higher International Society of Urological Pathology (ISUP) grades had higher infiltration levels of CD3⁺ T cells (P=0.023), CD8⁺ T cells (P=0.045), PD-1⁺ T cells (P=0.014), CD20⁺ B cells (P=0.020) and CD79⁺ B cells (P=0.049), and lower levels of Tryptase⁺ cells (P=0.001). Patients with abundant infiltrating immune cells tended to have better responses to immunotherapy. CONCLUSIONS The infiltrating immune cells are heterogeneous in Chinese ccRCC patients, and immune cell infiltration characteristics are closely correlated with clinicopathological parameters of the patients.
Humans ; Carcinoma, Renal Cell/pathology* ; Kidney Neoplasms/pathology* ; Immunotherapy ; Male ; Lymphocytes, Tumor-Infiltrating/immunology* ; Female ; Middle Aged ; CD8-Positive T-Lymphocytes/immunology* ; Aged ; T-Lymphocytes/immunology* ; Programmed Cell Death 1 Receptor/immunology* ; Adult ; CD4-Positive T-Lymphocytes/immunology* ; Neoplasm Staging

Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). This study investigates the role of high mobility group box 1 (HMGB1) in oligodendrocyte precursor cells (OPCs) in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier (BBB) by using OPC-specific HMGB1 knockout (KO) mice. We found that HMGB1 released from OPCs promotes BBB disruption, subsequently allowing increased immune cell infiltration. The migration of CD4+ T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes (OLs). OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS, leading to less damage to the myelin sheath and mitigated EAE progression. CD4+ T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs. Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; HMGB1 Protein/deficiency* ; Mice, Knockout ; Oligodendrocyte Precursor Cells/immunology* ; Mice, Inbred C57BL ; CD4-Positive T-Lymphocytes/immunology* ; Cell Movement ; Blood-Brain Barrier/immunology* ; Mice ; Myelin Sheath/pathology* ; Disease Models, Animal ; Coculture Techniques ; Oligodendroglia/metabolism* ; Female ; Cells, Cultured

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4⁺ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4⁺ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.
Animals ; Humans ; Mice ; CD4-Positive T-Lymphocytes/pathology* ; Cell Differentiation ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Mice, Inbred C57BL ; Multiple Sclerosis ; Th1 Cells/pathology*

OBJECTIVES: To explore the prophylactic and therapeutic effects of Alhagi maurorum ethanolic extract (AME) in concanavalin A (Con A)-induced hepatitis (CIH) as well as possible underlying mechanisms. METHODS: Polyphenols in AME were characterized using high performance liquid chromatography (HPLC). Swiss albino mice were divided into 4 groups. Normal group received intravenous phosphate-buffered saline (PBS); Con A group received 40 mg/kg intravenous Con A. Prophylaxis group administered 300 mg/(kg·d) AME orally for 5 days before Con A intervention. Treatment group received intravenous Con A then administered 300 mg/kg AME at 30 min and 3 h after Con A intervention. After 24 h of Con A injection, hepatic injury, oxidative stress, and inflammatory mediators were assessed. Histopathological examination and markers of apoptosis, inflammation, and CD4⁺ cell infiltration were also investigated. RESULTS: HPLC analysis revealed that AME contains abundant polyphenols with pharmacological constituents, such as ellagic acid, gallic acid, ferulic acid, methylgallate, and naringenin. AME alleviated Con A-induced hepatic injury, as manifested by a significant reduction in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase (P<0.01). Additionally, the antioxidant effect of AME was revealed by a significant reduction in oxidative stress markers (nitric oxide and malondialdehyde) and restored glutathione (P<0.01). The levels of proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, and interleukin-6) and c-Jun N-terminal kinase (JNK) activity were reduced (P<0.01). Histopathological examination of liver tissue showed that AME significantly ameliorated necrotic and inflammatory lesions induced by Con A (P<0.01). Moreover, AME reduced the expression of nuclear factor kappa B, pro-apoptotic protein (Bax), caspase-3, and CD4⁺ T cell hepatic infiltration (P<0.01). The expression of anti-apoptotic protein Bcl-2 was increased (P<0.01). CONCLUSION AME has hepatoprotective and ameliorative effects in CIH mice. These beneficial effects are likely due to the anti-inflammatory, antioxidant, and anti-apoptotic effects of the clinically important polyphenolic content. AME could be a novel and promising hepatoprotective agent for managing immune-mediated hepatitis.
Animals ; Concanavalin A ; Mice ; Polyphenols/pharmacology* ; Liver/drug effects* ; Plant Extracts/therapeutic use* ; Camelus ; Oxidative Stress/drug effects* ; Male ; Protective Agents/pharmacology* ; Chemical and Drug Induced Liver Injury/prevention & control* ; Apoptosis/drug effects* ; Hepatitis/pathology* ; Antioxidants/pharmacology* ; CD4-Positive T-Lymphocytes/drug effects* ; Inflammation Mediators/metabolism*

Animals ; Asthma/pathology* ; CD4-Positive T-Lymphocytes/immunology* ; China/epidemiology* ; Disease Models, Animal ; Immunoglobulin E/blood* ; Incidence ; Lung/pathology* ; Mice ; Pollen/chemistry* ; Populus/adverse effects* ; Prevalence

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

Objective To explore the clinical and laboratory characteristics and the prognosis of disseminated non-tuberculous mycobacteria(NTM)diseases in human immunodeficiency virus(HIV)negative patients. Methods Cases of disseminated NTM disease were retrospectively collected in Peking Union Medical College Hospital from January 2012 to October 2018.Clinical manifestations,laboratory findings,treatment,and prognosis of these cases were retrieved from the electronic medical record system. Results Among the 23 HIV negative patients with disseminated NTM disease,21 had underlying diseases,with rheumatoid immune disease(n=7)as the most common one.The main clinical manifestation was fever(n=23).Laboratory tests showed anemia [hemoglobin(85.78±25.47)g/L],hypoalbuminemia [albumin 29(27-32)g/L],elevated erythrocyte sedimentation rate [(85.73±43.78)mm/h] and hypersensitive C-reactive protein [(112.00±70.90)mg/L],and reduction of lymphocyte count [0.69(0.29-2.10)×10 /L].Lymphocyte subset analysis indicated reduction in CD4 T cells [213(113-775)/μl],CD8 T cells [267(99-457)/μl],B cells [39(4-165)/μl],and NK cells [88(32-279)/μl] and elevation of human leukocyte antigen-D related(HLA-DR),and CD38 expression in CD8 T cells [HLA-DR CD8 /CD8 ,60(40-68)%;CD38 CD8 /CD8 ,81(65-90)%].The most common species of NTM was Mycobacterium intracellular(n=6).Lymphocyte,CD8 T cell,B cell,and NK cell counts were significantly lower in dead patients than surviving patients(P =0.045,P=0.045,P=0.032,and P=0.010,respectively). Conclusions Disseminated NTM disease in HIV negative patients is mainly manifested as fever,anemia,hypoalbuminemia,and elevated inflammatory indicators.It is more likely to occur in immunocompromised patients.Patients with decreased lymphocytes,CD8 T cells,B cells and NK cells tend to have a poor prognosis.
Anemia ; B-Lymphocytes ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Fever ; HIV Seronegativity ; Humans ; Hypoalbuminemia ; Killer Cells, Natural ; Mycobacterium Infections, Nontuberculous ; diagnosis ; pathology ; Prognosis ; Retrospective Studies

Metastasis is the leading cause of death in breast cancer patients. However, the mechanisms underlying metastasis are not well understood and there is no effective treatment in the clinic. Here, we demonstrate that in MMTV-PyMT, a highly malignant spontaneous breast tumor model, IL-25 (also called IL-17E) was expressed by tumor-infiltrating CD4 T cells and macrophages. An IL-25 neutralization antibody, while not affecting primary tumor growth, substantially reduced lung metastasis. Inhibition of IL-25 resulted in decreased type 2 T cells and macrophages in the primary tumor microenvironments, both reported to enhance breast tumor invasion and subsequent metastasis to the lung. Taken together, our data suggest IL-25 blockade as a novel treatment for metastatic breast tumor.
Animals ; Antibodies, Neoplasm ; pharmacology ; Antibodies, Neutralizing ; pharmacology ; Breast Neoplasms ; drug therapy ; genetics ; immunology ; CD4-Positive T-Lymphocytes ; immunology ; pathology ; Female ; Humans ; Interleukin-17 ; antagonists & inhibitors ; genetics ; immunology ; Interleukins ; antagonists & inhibitors ; genetics ; immunology ; Macrophages ; immunology ; pathology ; Mammary Neoplasms, Animal ; drug therapy ; genetics ; immunology ; Mice ; Neoplasm Metastasis ; Tumor Microenvironment ; drug effects ; genetics ; immunology

The mechanism underlying CD4CD25Foxp3regulatory T cells (Tregs) promoting the development of colorectal cancer (CRC) was elucidated in the present study. Forty-eight cases of colorectal carcinomas, 22 cases of colon polyps and 21 cases of normal colorectal tissues were collected. The correlation among Foxp3, IL-10 and Stat3, and the clinical relevance of these three indexes were analyzed. The results showed that the levels of Foxp3 expressed in infiltrating CD4CD25Foxp3Tregs, and IL-10 and Stat3 in CRC tissues were all significantly higher than those in polypus tissues and normal colon tissues (P< 0.01). Pearson correlation analysis indicated that the expression level of Foxp3 was positively correlated with Stat3 at mRNA level (r=0.526, P=0.036), and was positively correlated with IL-10 at protein level (r=0.314, P=0.030). The Foxp3 expressed in CD4CD25Foxp3Tregs was correlated with the histological grade, lymph node metastasis and TNM stage of CRC (P<0.05 for all). The IL-10 expression was correlated with the histological grade and TNM stage (both P<0.05). The Stat3 expression was correlated with the lymph node metastasis and TNM stage (both P<0.05). It was concluded that CD4CD25Foxp3Tregs can inhibit tumor immunity in combination with some other related inhibitory cytokines and that Foxp3 expression in CD4CD25Foxp3Tregs correlates with CRC progression.
Adult ; Aged ; CD4-Positive T-Lymphocytes ; immunology ; Colorectal Neoplasms ; genetics ; immunology ; pathology ; Female ; Forkhead Transcription Factors ; biosynthesis ; genetics ; immunology ; Gene Expression Regulation, Neoplastic ; immunology ; Humans ; Immunity ; genetics ; Interleukin-10 ; biosynthesis ; immunology ; Interleukin-2 Receptor alpha Subunit ; immunology ; Lymphatic Metastasis ; Male ; Middle Aged ; STAT3 Transcription Factor ; biosynthesis ; immunology ; T-Lymphocytes, Regulatory ; immunology

OBJECTIVETo observe the expression of peripheral blood CD4+ T lymphocyte apoptosis gene in rheumatoid arthritis (RA) patients with cold dampness type (CDT), and to explore its correlation with clinical indicators of RA.

METHODSSixteen RA patients with CDT (as the RA group) and 16 healthy subjects (as the normal control group) were recruited. CD4 T cell apoptosis rate was detected in the RA group and the normal control group using FCM. mRNA expressions of fas, fasL, caspase-3, caspase-8, bcl-2, and bax were detected using RT-PCR. Correlations between the expression of apoptosis gene and clinical activity indicators of RA (ESR, CRP, RF, CCP, integrals for Chinese medial symptoms, morning stiffness time, joint tenderness number, joint swelling number, DAS28-3) were analyzed.

RESULTSThe apoptosis rate of CD4+ T was significantly lower in the RA group than in the control group [(2. 6 +/- 0.9) % vs. (7.7 +/- 1.3) %, P < 0.01]. mRNA expression levels of fas, fasL, caspase-8, caspase-3, and bax mRNA of CD4+ T significantly decreased, but bcl-2 mRNA expression increased in the RA group (P < 0.01). The apoptosis rate of CD4+ T was negatively correlated with ESR (P < 0.05). The mRNA expression of caspase-8 was negatively correlated with joint swelling number (P < 0.05). The mRNA expression of bcl-2 was negatively correlated with integrals for Chinese medial-symptoms and joint function classification (P < 0.01, P < 0.05).

CONCLUSIONApoptosis obstacle exists in peripheral blood CD4 +T lymphocyte of RA patients, and is closely related to disease activity.

Apoptosis ; Arthritis, Rheumatoid ; diagnosis ; metabolism ; pathology ; CD4-Positive T-Lymphocytes ; Caspase 3 ; metabolism ; Caspase 8 ; metabolism ; Fas Ligand Protein ; Humans ; RNA, Messenger