T-cell Subgroups Research Articles

The Predictive Value of T-Lymphocyte Subset Distribution for the Occurrence and Prognosis of Atrial Fibrillation

Introduction: The effect of T lymphocytes on atrial fibrillation (AF) is still unclear. We aimed to assess the associations between the T-lymphocyte subgroup distribution and incident AF and AF prognosis. Methods: Consecutive patients were enrolled from June 2020 to October 2021. Their T-cell subgroups, including CD3, CD4, and CD8 T cells, and the CD4/CD8 ratio (CDR) were measured. We assessed the relationships between the CDR and composite endpoints, including hospitalization due to heart failure, stroke or systemic embolism, and cardiovascular mortality rates. Results: A total of 45,905 patients, among whom 818 had AF, were enrolled. The proportions of the T-lymphocyte subgroups CD3 (OR: 0.9995; 95% CI: 0.9993–0.9997, p < 0.001), CD4 (OR: 0.9995; 95% CI: 0.9991–0.9998, p = 0.004), and CD8 (OR: 0.9988; 95% CI: 0.9984–0.9992, p < 0.001) and the CDR (OR: 1.2714; 95% CI: 1.1355–1.4165, p < 0.001) were correlated with AF incidence. The CDR was associated with AF incidence (OR: 1.1998; 95% CI: 1.0746–1.3336, p < 0.001) after adjustment. High CDR was associated with a higher rate of hospitalization due to heart failure (HR: 3.45; 95% CI: 1.71–6.96, p < 0.001), stroke, or systemic embolism (HR: 2.54; 95% CI: 1.32–4.91, p = 0.005), and cardiovascular mortality (HR: 2.25; 95% CI: 1.05–4.84, p = 0.038). There was no significant difference in all-cause mortality between CDR strata (HR: 1.61; 95% CI: 0.90–2.87, p = 0.111). Conclusion: Elevated CDR was positively associated with the incidence and prognosis of AF. This finding may help improve the prevention and treatment of AF.

T Cells Immune Imbalance Present in Patients With Multiple Intracranial Aneurysms.

Growing evidence suggests that systemic immune and inflammatory responses may play a critical role in the formation and development of aneurysms. Exploring the differences between single intracranial aneurysm (SIA) and multiple IAs (MIAs) could provide insights for targeted therapies. However, there is a lack of comprehensive and detailed characterization of changes in circulating immune cells in MIAs. Peripheral blood mononuclear cell (PBMC) samples from patients with SIA (n = 16) or MIAs (n = 6) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. A total of 25 cell clusters were identified, revealing that the immune signature of MIAs included cluster changes. Compared to patients with SIA, patients with MIAs exhibited immune dysfunction and regulatory imbalance in T-cell clusters. They also had reduced numbers of CD8+ T cells and their subgroups CD8+ Te and CD8+ Tem cells, as well as reduced numbers of the CD4+ T-cell subgroup CD27-CD4+ Tem cells. Furthermore, compared to SIA, MIAs were associated with enhanced T-cell immune activation, with elevated expression levels of CD3, CD25, CD27, CCR7, GP130, and interleukin 10. This study provides insights into the circulating immune cell profiles in patients with MIAs, highlighting the similarities and differences between patients with SIA and those with MIAs. Furthermore, the study suggests that circulating immune dysfunction may contribute to development of MIAs.

Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children

Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vβ21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vβ21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vβ21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells.

Transplantation of a bioengineered tissue patch promotes uterine repair in the sheep.

Innovative bioengineering strategies utilizing extracellular matrix (ECM) based scaffolds derived from decellularized tissue offer new prospects for restoring damaged uterine tissue. Despite successful fertility restoration in small animal models, the translation to larger and more clinically relevant models have not yet been assessed. Thus, our study investigated the feasibility to use a 6 cm2 graft constructed from decellularized sheep uterine tissue, mimicking a future application to repair a uterine defect in women. Some grafts were also recellularized with fetal sheep bone marrow-derived mesenchymal stem cells (SF-MSCs). The animals were followed for six weeks post-surgery during which blood samples were collected to assess the systemic immune cell activation by fluorescence-activated cell sorting (FACS) analysis. Tissue regeneration was assessed by histology, immunohistochemistry, and gene expression analyses. There was a large intra-group variance which prompted us to implement a novel scoring system to comprehensively evaluate the regenerative outcomes. Based on the regenerative score each graft received, we focused our analysis to map potential differences that may have played a role in the success or failure of tissue repair following the transplantation therapy. Notably, three out of 15 grafts exhibited major regeneration that resembled native uterine tissue, and an additional three grafts showed substantial regenerative outcomes. For the better regenerated grafts, it was observed that the systemic T-cell subgroups were significantly different compared with the failing grafts. Hence, our data suggest that the T-cell response play an important role for determining the uterus tissue regeneration outcomes. The remarkable regeneration seen in the best-performing grafts after just six weeks following transplantation provides compelling evidence that decellularized tissue for uterine bioengineering holds great promise for clinically relevant applications.

Alterations in oxidative stress biomarkers and helper T-cell subgroups in patients with periodontitis and IgA nephropathy.

Investigating the changes in the oxidative stress levels and helper T lymphocyte (Th) subsets in patients with periodontitis and IgA nephropathy (IgAN) to determine their relationship. IgAN has a high prevalence, poor prognosis, and no effective cure. Accumulating evidence has implicated a close relationship between periodontitis and chronic kidney diseases, in which both IgAN and chronic periodontitis show chronic inflammation and abnormal metabolism. However, few studies have been conducted on the relationship between the two diseases from this perspective. We divided 86 IgAN patients into patients with healthy periodontium (IgAN-H, n = 34) and patients with periodontitis IgAN (IgAN-P, n = 52); moreover, we divided 72 systemically healthy participants into patients with periodontitis (H-P, n = 35) and participants with healthy periodontium (H-H, n = 37). The proportions of Th subsets in peripheral blood were estimated using flow cytometry. Cytokine levels in plasma were assessed using cytokine assay kits. Enzyme-linked immunosorbent assay was used to evaluate the plasma levels of oxidative stress. Our results from analyzing the Th cell subsets indicated that Th2 cell counts in the IgAN-P group were significantly lower than those in the IgAN-H group, while Th17 cell counts were increased (p < 0.05). Moreover, the Th1/Th2 ratio and interleukin-6 levels in the IgAN-P group were significantly higher than those in the H-H group (p < 0.01). Compared with that in the H-H group, in the remaining three groups, plasma total oxidation state (TOS) levels were increased (p < 0.01), while plasma total antioxidant state (TAS) levels were decreased (p < 0.05). Furthermore, estimated glomerular filtration rate was negatively correlated with the probing depth and gingival bleeding index. IgAN was a risk factor for periodontitis, while TAS was a protective factor for periodontitis. The oxidative stress index (OSI) might be valuable for distinguishing periodontitis patients from healthy controls (area under the receiver operator characteristic curve = 0.951). IgAN is an independent risk factor of periodontitis, and the Th17 cell-mediated inflammatory response might be associated with the occurrence of periodontitis in patients with IgAN. Patients with coexisting IgAN and periodontitis exhibit increased oxidative stress, in which TOS and OSI are potential biomarkers for diagnosing periodontitis.

Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype.

Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.

Efficacy of Pretreatment with Lycium barbarum Polysaccharide in Various Doses in Influencing Splenic Immunity and Prognosis of Sepsis in Rats.

Objective Sepsis, showing high mortality, is a lethal dysfunction of organs caused by an infection-induced disorder in the host response. It has complicated pathogenesis, which has not yet been elucidated completely. Recently, the principal factors causing pathogenesis and even death in sepsis patients are imbalance in inflammatory response and immunosuppression occurring when the host is challenged by infection. Previous studies found that Lycium barbarum polysaccharide (LBP) worked well in enhancing immunity. This study aims at exploring the efficacy of pretreatment with LPB in regulating splenic immunity during the pathogenesis of sepsis induced by cecum ligation perforation (CLP) in rats. Methods This research established the cecum ligation perforation rat model. Using immunohistochemistry and flow cytometry, the effects of Lycium barbarum polysaccharide in various doses in influencing splenic immunity and prognosis of sepsis induced by cecum ligation perforation in rats were examined. Results This study showed that LBP lowered the 72-hour mortality of sepsis rats induced by CLP, relieved systemic inflammation, improved the ratio of T-cell subgroups positive in CD3+, CD4+, or CD8+ and expression of HLA-DR protein, and repaired damage to splenic tissue, implying its efficacy in enhancing the immunity of sepsis rats induced by CLP. Conclusions LBP may ameliorate clinical symptoms of rats with cecum ligation perforation, improve cellular immunity in the spleen, and treat sepsis so as to provide a theoretical basis for the pathogenesis and development of sepsis as well as its diagnosis and treatment, and offer scientific proof for the development and utilization of LBP applied to critical diseases.

Environmental exposures and lymphoma risk: a nested case–control study using the Golden Retriever Lifetime Study cohort

Lymphoma is the second most common cancer affecting Golden Retrievers and is hypothesized to arise through a complex interaction of genetic and environmental factors. The aim of this nested case–control study was to investigate the association between potential environmental pollutant sources and lymphoma risk among Golden Retrievers participating in the Golden Retriever Lifetime Study. Forty-nine Golden Retrievers with non-cutaneous lymphoma and 98 Golden Retrievers without a history of cancer matched by age, sex and neuter status were selected from the Golden Retriever Lifetime Study cohort. Geographic proximity between each dog’s primary residence and nine potential sources of environmental pollution was determined. In addition, the average annual ozone and airborne fine particulate matter levels for each dog’s county of residence and owner-reported secondhand smoke exposure were evaluated. Environmental pollution sources of interest included chemical plants, municipal dumps, manufacturing plants, incineration plants, railroad embankment tracks, landfills, coal plants, high-voltage transmission lines, and nuclear power plants. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each exposure of interest. Subgroup analyses were conducted to evaluate whether associations differed among 1) dogs with multicentric lymphoma, 2) dogs with B-cell lymphoma, and 3) dogs with T-cell lymphoma. No variables reached statistical significance when evaluating all cases together. However, cumulative exposure burden (household proximity to 3 or more pollution sources) approached significance within the multicentric lymphoma subgroup (OR = 2.60, 95%CI 0.99–6.86, p-value = 0.053). Patterns emerged among B- and T-cell subgroups, but none reached statistical significance. Ongoing research is warranted to discern if different environmental mechanisms may be driving B- and T-cell lymphoma immunophenotypes, consistent with previously reported regional differences in subtype prevalence.

The effect of acupoint stimulation on T lymphocyte subsets and NK cells in cancer patients: A systematic review and meta-analysis

IntroductionAcupoint stimulation (AS) is used in treating patients with cancer for a variety of indications and may affect the body's immune function. This systematic review aimed to investigate the effects of clinical AS on T-lymphocyte subsets and natural killer (NK) cells in patients with malignant tumors. MethodsA search was conducted for randomized controlled trials (RCT) published between 1.1.1990 and 10.2. 2020 in English, Chinese, Korean and Japanese databases. RCTs were included if the studies had: more than 30 participants, the control was placebo/usual care, AS was the primary intervention and a primary outcome of T-cell subgroup percentage or NK cell percentage was measured by peripheral blood flow cytometry. A random-effects model was applied where I2≥50%, as heterogeneity was high. For other cases, the fixed-effects model was applied. ResultsA total of 18 studies with 980 patients were included in the systematic review. The results showed that AS could significantly increase the number of CD4+ cells in the peripheral blood of all patients with cancer (chemotherapy group: mean difference (MD): 2.58; 95% CI: 0.09–5.08, I2 = 77%; and non-chemotherapy group: MD: 6.46; 95% CI: 2.12–10.80, I2 = 90%). In the non-chemotherapy group, AS could increase the number of CD3+ cells (MD: 9.34; 95% CI: 5.26–13.41, I2 = 84%), and NK cells (MD: 5.88; 95% CI: 0.90–10.86, I2 = 94%) in the peripheral blood. In addition, acupuncture could increase the number of CD3+ (MD: 12.21; 95% CI: 3.79 to 20.64, I2 = 91%), CD4+ (MD: 7.68; 95% CI: 0.31 to 15.04, I2= 88%) and CD8+ (MD: 2.55; 95% CI: 0.55 to 4.55, I2 = 0%) cells., while warm acupuncture could significantly increase the number of NK cells (MD: 2.58; 95% CI: 1.20–3.96, I2 = 0%). However, the incomplete record of the adverse effects, the difference in frequency and duration of AS and the low evidence level limited our conclusion. ConclusionAS increased the number of CD4+ cells in the peripheral blood and moderated other immune cells benefiting the immune system of patients with cancer. (PROSPERO ID is CRD42020167842).

Immune Profiling of Relapsed/Refractory Multiple Myeloma Patients Treated with Venetoclax in Combination with Dexamethasone (VenDex), Daratumumab and Dexamethasone (VenDd), and Daratumumab, Bortezomib and Dexamethasone (VenDVd)

Background: The BCL-2 family of anti-apoptotic proteins (e.g., BCL-2, BCL-XL, MCL-1) are important regulators of lymphocyte development and are therapeutic targets for hematologic malignancies, including multiple myeloma (MM). Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in MM cells and has shown synergistic activity with bortezomib (Velcade; V) and dexamethasone (Dex or d). Combination of the CD38 monoclonal antibody (mAb) daratumumab (D) with Ven is hypothesized to further increase anti-myeloma activity based upon dual mechanisms of pro-apoptotic effects on tumor cells as well as enhanced immune stimulation. Pre-clinically and in healthy human subjects, Ven treatment leads to enrichment of CD8+ T effector memory cells, while resulting in loss of CD4+ and CD8+ naïve T-cells, however the potential immunomodulatory effect of Ven in MM is unknown. Results presented herein describe the pharmacodynamic changes observed in immune cell subsets in relapsed/refractory (R/R) MM patients (pts) treated with VenDex, VenDd, and VenDVd. Methods: Peripheral blood samples were collected at day 1 of cycles 1-5 to characterize pharmacodynamic changes in B- and T-cell sub-populations by multicolor flow cytometry in Ven MM clinical trials M13-367 (NCT01794520) and M15-654 (NCT03314181). M13-367 is a phase 1/2 study of VenDex in t(11;14) R/R MM, and M15-654 is a phase 1/2 study of VenDd in t(11;14) R/R MM (Part 1) and VenDVd in R/R MM (Part 2). As of 12 June 2019, 15 out of 31 pts treated with VenDex in phase 2 of M13-367, 19 out of 24 pts treated in Part 1 (VenDd), and 19 out of 24 pts treated in Part 2 (VenDVd) of M15-654 had baseline and post-treatment specimens available for analysis. Results: Consistent with previous findings that B-cells are highly dependent upon BCL-2 for cell survival, each Ven-containing regimen (VenDex, VenDd, and VenDVd) resulted in rapid and sustained reduction (~90% decrease from baseline by end of cycle 1) in peripheral B-cell (CD19+/CD5-) counts (Figure). In subgroup analyses, naïve B-cells (CD27-/IgM+) were significantly reduced in pts treated with each regimen, however regulatory B-cells (CD27+/CD24+) remained largely unaffected. In addition, a decrease in plasmablasts (CD27+CD38+CD20-) were only observed in pts treated with D-containing regimens (VenDd and VenDVd), which is consistent with expression of CD38 in this subgroup. In contrast to B-cells, CD3+ T-cells were minimally reduced (~20-30% reduction from baseline through end of cycle 4) with VenDex and VenDd treatment. A more prominent reduction was observed in pts treated with VenDVd (~50-60% reduction from baseline through end of cycle 4). CD4+ T-cells were more sensitive than CD8+ T-cells to VenDex and VenDd, while both CD4+ and CD8+ T-cells were reduced in VenDVd treated pts (Figure). T-cell subgroup analyses were also performed, including naïve T-cells (CD45RA+/CD197+), effector (CD45RA+/CD197-), effector memory (CD45RA-/CD197-), and central memory (CD45RA-/CD197+). Overall, there were no significant changes in the composition of the T-cell pool (Tnaive, TCM, TEM, TEMRA) or in Th1 (CD4+/CD183+/CD196-), Th2 (CD4+/CD183-/CD196-), and Th17 (CD4+/CD183-/CD196+) cells in pts treated with VenDex, VenDd, or VenDVd. Finally, a decrease in Tregs (CD4+/CD25+/CD127low/CD194+) was observed in VenDd and VenDVd treated pts, but not in VenDex treated pts (Figure). While no reduction in overall Tregs was observed with VenDex, a decrease in the relative proportion of activated Tregs (HLA-DR+/CD45RO+) to naïve (HLA-DR-/CD45RO-) and memory (HLA-DR-/CD45RO+) Tregs was observed. Conclusions: Comprehensive immunophenotyping studies were conducted to characterize the potential effects of Ven in B- and T-cell subsets when used in combination with standard of care anti-myeloma agents of various mechanisms of action (i.e. glucocorticoid, CD38 mAb and/or proteasome inhibitor). While each Ven combination regimen resulted in significant reductions in circulating B-cells, T-cell effects were largely dependent upon the combination regimen. Minimal reduction in total T-cell counts were observed with VenDex and VenDd, which were primarily due to reduction in CD4+ T-cells. However, the extent of T-cell depletion (CD4+ and CD8+ T-cells) was greatest in pts treated with the bortezomib-containing regimen VenDVd. Correlative studies between immune profiles and pt outcomes are ongoing. Disclosures Vishwamitra: AbbVie: Employment, Other: stock or other options. Mantis:AbbVie Inc: Employment, Other: Stock/stock options. Haribhai:AbbVie: Employment, Other: stock or other options. Uziel:AbbVie: Employment, Other: stock or other options. Leverson:AbbVie Inc: Employment, Other: Stock or options. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Bueno:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options.

Highly sensitive detection of CTLA-4-positive T-cell subgroups based on nanobody and fluorescent carbon quantum dots.

The detection of cytotoxic T-lymphocyte antigen-4-positive (CTLA-4+) T-cell subgroups in peripheral blood samples and tumor tissues is of great significance. In the present study, a rapid, succinct and efficient method was designed for the detection of CTLA-4+ human T cells using a CTLA-4-specific nanobody-fluorescent carbon quantum dots complex (QDs-Nb36). QDs-Nb36 was used for high sensitivity detection of CTLA-4+ T cells by flow cytometry or immumofluorescent staining. The present study demonstrated that the novel technique was more specific and effective in the detection of CTLA-4+ T-cell ratio in the peripheral blood and tumor tissues compared with a traditional monoclonal antibody approach. Furthermore, no significant toxicity was identified in vitro and in vivo, thus suggesting that the method may have broad applications for the detection of certain lowly expressed targets.

PD-1 Expression on Circulating CD8+ T-Cells as a Prognostic Marker for Patients With Gastric Cancer.

Programmed death-1 (PD1) is an immunoinhibitory receptor, and PD1 overexpression on T-cells is involved in immune evasion in cancer. This study investigated the prognostic significance of PD1 expression on T-cells in gastric cancer. PD1 expression on CD4+ and CD8+ T-cells obtained from peripheral blood mononuclear cells was evaluated by multicolor flow cytometry. Based on cutoff values from receiver operating characteristic analysis, patients were sub-grouped according to PD1 positivity as having high or low PD1+CD4+ T-cell (cutoff ≥34.2%) and PD1+CD8+ T-cell (cutoff ≥28.7%) frequencies. Five-year overall survival rates differed significantly between the groups with low and high frequency of PD1+CD4+ T-cells (75.1% vs. 27.2%, respectively; p=0.0008). The 5-year overall survival rates were 78.3% and 37.2%, respectively, for the corresponding PD1+CD8+ T-cell subgroups (p=0.0004). Multivariate analysis revealed that the frequency of PD1+CD8+ T-cells was an independent prognostic indicator. The frequency of PD1+CD8+ T-cells may predict the prognosis of patients with gastric cancer.

Dynamic and significant changes of T-cell subgroups in breast cancer patients during surgery and chemotherapy

ObjectiveBreast cancer and its surgical treatment and chemotherapy have great impact on the immune system. This study aimed to monitor the various T cells in breast cancer patients and evaluate the immune functions. MethodsBlood samples were collected from 249 breast cancer patients at the following time points: 1–3 days preoperative, postoperative (before the chemotherapy), after 3 chemotherapy cycles, and after 6 chemotherapy cycles. The percentages of the CD3+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells were measured using flow cytometry. Another 200 healthy women were used as control. ResultsPatients with stage II/III breast cancer had significantly lower percentages of CD3+, CD4+, CD8+, CD45RA+, and CD28+ T cells in comparison with normal control and those with stage I breast cancer (P < 0.05). The percentages of CD45RO+ T cells and CD4+CD25+ (Treg) cells were significantly higher in stage II/III malignancies versus stage I, and was significantly higher in stage I malignancies versus the normal control (P < 0.05). Breast cancer patients had significantly lower percentages of CD3+ and CD4+ T cells in comparison with the normal control (P < 0.05). The preoperative percentages of CD3+ and CD4+ T cells were significantly reduced after 3 cycles and after 6 cycles of chemotherapy (P < 0.05). In patients with stage II/III malignancies, there was a higher percentage of CD45RO+ T cells than CD45RA+ T cells, which was reversed after surgery. After 6 chemotherapy cycles, the percentage of Treg cells was significantly reduced in comparison with that before the chemotherapy in the patients with stage II/III malignancies. ConclusionsPatients with breast cancer had significantly suppressed immune functions. Surgical removal of the tumor may improve the immune functions. Chemotherapy significantly reduced the percentages of CD3+ and CD4+ T cells.

Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A systematic review and meta-analysis.

The potential prognostic value of tumor-infiltrating lymphocytes (TILs) in gastric cancer remains controversial. This meta-analysis examines the association between TILs and survival outcomes in gastric cancer. Twenty-two eligible studies were identified using the PubMed and Google Scholar databases. The combined sample size of the 22 studies was 2941, and the median sample size of the individual studies was 122 patients (52-220). The main clinical outcomes examined were overall cancer survival (OCS) and overall cancer relapse-free survival (OCRFS). Tumor tissue CD3(+) TILs, indicative of pan-T-cell expression, had a positive effect on survival with a hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.52-0.78) for OCS, as did the non-FOXP3(+) T-cell subgroup with an HR of 0.66 (95% CI 0.57-0.75), particularly in CD8(+) lymphocytes (HR = 0.63, 95% CI 0.48-0.83). On the contrary, high FOXP3(+) T-cell expression was correlated with reduced OCS, with an HR of 1.75 (95% CI 1.26-2.42). Analysis of the seven studies evaluating OCRFS revealed improved OCRFS with infiltration of non-FOXP3(+) TILs with an HR of 0.59 (95% CI 0.42-0.81) but not FOXP3(+) T lymphocytes with an HR of 1.82 (95% CI 1.30-2.53). The results from this meta-analysis suggest that high expression of TILs, mainly by CD8 lymphocytes, may be a potential prognostic biomarker in patients with gastric cancer.

Porcine endothelial grafts could survive for a long term without using systemic immunosuppressors: An investigation of feasibility and efficacy of xeno-Descemet's stripping automated endothelial keratoplasty from WZS-pig to rhesus monkey.

In current non-human primate models, full-thickness porcine grafts could not achieve long-term survival without using potent systemic immunosuppressors. Moreover, the thickness disparity in xeno-PKP proved to be hard to manipulate and may cause several complications which also could prevent the grafts from long survival. Considering the advantages of Descemet's stripping automated endothelial keratoplasty (DSAEK) derived from its ultrathin graft and lower rejection rate, we hypothesize xeno-DSAEK may overcome these imperfections in xeno-PKP. The aim of this study was to explore the feasibility and efficacy of xeno-DSAEK and to investigate the possibility of long-term survival of porcine DSAEK grafts only using local immunosuppressors. Nine rhesus monkeys were divided into two groups. In the DSAEK group (n=7), Descemet's membrane stripping was performed to establish the bullous keratopathy model followed by the endothelial graft transplant. In the control group (n=2), only DM stripping was performed. Betamethasone 3.5mg was injected subconjunctivally every 10 days for a total of 10 times in the DSAEK group. After the surgery, all grafts were evaluated by slit lamp microscopy for at least 6months. In addition, anterior segment optical coherence tomography (AS-OCT) and confocal laser microscopy (CLM) were hired to evaluate the graft attachment and survival. To investigate the rejection mechanism for xeno-DSAEK, pathological and immunity examinations, including immunohistochemistry, immunofluorescence, T-cell subgroups, cytokine concentration, and anti-GAL antibodies, were performed and compared between the survived and rejected grafts. In the control group, the corneal opacity gradually increased with the development of corneal swelling and neovascularization. In the DSAEK group, five recipients (n=5/7) re-established their transparencies within 30days after xeno-DSAEK, and four grafts survived >180days (>180, >180, >298, >270) only by injecting betamethasone subconjunctivally, whereas two grafts (n=2/7) rejected in 30days. The AS-OCT and CLM showed the survived grafts attached firmly to the host beds, and the endothelial cell density was adequate (>2000cells/mm2 ) to maintain the graft function at post-operative month 6. The immunohistochemistry showed predominantly T cells (CD4+ and CD8+) and macrophages infiltrated in the rejected grafts, although a few B cells (CD20+) were also observed. Moreover, immunofluorescence demonstrated donor-specific antibody (IgG) and complement (C3c) were also involved in the immune rejection. However, T-cell subgroups and cytokine concentrations (except for IL-6) showed no significant differences between the rejected and survived grafts. Xeno-DSAEK is feasible and effective, and the technique may reduce the complications common to xeno-PKP. More importantly, the porcine DSAEK grafts could survive for a long term without using systemic immunosuppressors and exhibit promising future for clinical practice.

Research progress of follicular cytotoxic T cells in HIV infection

Abstract Recently, a new type of CD8+ T-cell subset, namely, the chemokine (C-X-C motif) receptor 5 (CXCR5+) cluster of differentiation (CD8+) T-cell subset (also called the follicular cytotoxic T-cell (TFC) subgroup), has been discovered around B-cell follicles. The discovery has aroused widespread interest. However, the processes and mechanisms of TFCs taking part in the immune response of the germinal center and their specific roles must still be clearly identified. This article reviews domestic and foreign studies on factors regulating the phenotype, physiological functions, maturity, and differentiation of TFCs and roles and clinical significance of these cells in HIV infection. This review has shown good application prospects for TFCs. The author believes that further studies on TFCs can provide another tool for cytotherapy to control or cure chronic viral infections or tumors.

Proteomic Analysis and Immunoregulation Mechanism of Wheat Germ Globulin.

Wheat germ, one of the byproducts of flour milling, contains abundant physiologically active components. Globulins in wheat germ are a class of high-quality functional proteins and have received widespread attention. However, the composition of wheat germ globulin（ WGG）and the structure of the typical proteins have not yet been proved. The immunological activities and immune mechanisms of the WGG have not yet been revealed in vivo. The proteomic analysis of WGG and the structure simulation of typical proteins were studied. The immunoregulatory effects of WGG on immunosuppressed mice induced by cyclophosphamide were investigated, and the immunological activities of WGG were explored. The main components, functions, and metabolic signaling pathways of WGG were analyzed through a combination of LC-MS method and bioinformatics. The structure of WGG was predicted via the Phyre2 tool. Immunosuppression in mice was induced by cyclophosphamide. After an intraperitoneal injection of WGG for 10 days, organ indexes and pathological changes of mice were detected. The T-cell subgroups in peripheral blood were analyzed via flow cytometry. Levels of IL-2, IL-4, TNF-α, and IFN-γ were evaluated through ELISA. The mRNA expression levels of T-Bet and GATA-3 were measured using real-time PCR. The results indicated that the main functional components of WGG were wheat germ globulins, histones, heat shock proteins (HSPs), and other functional proteins. Wheat germ globulins and HSPs were the major immune components of WGG. WGG significantly reduced immunosuppression in the spleen and thymus indexes (P<0.01), and mitigated the damage caused by cyclophosphamide in the spleen and thymus. Moreover, WGG significantly increased the CD4+/CD8+ of the immunosuppressed mice (P<0.01), restored Th1/Th2 imbalance (P < 0.01), enhanced the content of IL-2 and IL-4 (P<0.01), and modified the abnormal secretion of cytokines. WGG also observably reduced the mRNA expression of T-Bet and GATA-3 (P<0.01). These results manifested that WGG components improved the immune system. The action mechanisms might be related to the variation of Th1/Th2 cells resulted from the control of the mRNA expression levels of T-Bet and GATA-3. The wheat germ histone family and the HSPs are the major immune components of WGG. It may be the immune mechanism of WGG that these globulins affect the differentiation of Th1/Th2 cells via controlling the mRNA expression levels of related genes. The results indicated the potential application of WGG or its further purified products as a superior plant-derived immunomodulator in the future.

Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer.

The incidence and development of cancer are closely related to dysfunction of immune function. The immune system cannot identify and remove malignant and mutant cells, which cause tumor cells to escape from surveillance and clearance of the immune system. Immunobiological cancer therapy plays an important role in strengthening body immunological surveillance function and killing remaining tumor cells in the body. We investigated the role of DC/CIK (dendritic cell/cytokine-induced killer cells) immunobiological cancer therapy in maintenance therapy of advanced non-small cell lung cancer. When 60 cases of non-small cell lung cancer patients in stage IIIb and IV reached stable disease after treatment with 4 cycles of a two-drug regimen with platinum, they were randomly divided into two groups. One group was treated with DC/CIK immunobiological cancer therapy, and the other was taken as a control group. Finally, cancer progression time and toxicity reaction of the two groups were evaluated. DC/CIK treatment prolongs progression-free survival (3.20 months [95% CI, 2.94-3.50] vs 2.56 months [95% CI, 2.39-2.73]; P <0.05). In the treatment group, the proportion of NK cells, T-cell subgroups CD3+, CD4+ and CD8+ had a significant change before and after treatment. Liver and kidney function and blood tests of the treatment group were within the normal range before and after treatment. In the treatment group, 1 case suffered from chest distress, 3 cases suffered from acratia, and 4 cases suffered from pyrexia. DC/CIK treatment had potential benefit for patients with advanced non-small cell lung cancer compared with the control group and had no obvious side effects. DC/CIK treatment is a safe and effective method for maintenance therapy of advanced non-small cell lung cancer.

More significance of TB-IGRA except for the diagnose of tuberculosis.

Tuberculosis (TB)-interferon gamma release assay (IGRA) test has the characteristics of short time, high specificity, and high sensitivity, but it lacks the correlation research between TB-IGRA test results and body's immune cells, disease progression and prognosis, which is explored in this study. A retrospective study was carried out on positive TB-IGRA patients who were infected with TB and diagnosed at our hospital from January 2014 to June 2015. The TB-IGRA, routine blood test, T-cell subgroup data were collected for statistical analysis. TB-IGRA results were in positive proportion to the lymphocytes, CD4+ T cells and CD4+ CD28+ T cells, whereas negative to the Treg cells. Patient with unilateral pulmonary lesion had higher TB-IGRA than those with bilateral pulmonary lesions. After the stimulation of TB-specific antigen, the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T Tcells were both increased and the CD4+ IFN-γ+ T had positive correlation with the value of TB-IGRA. IFN-γ was tested with TB-IGRA in patients with TB by the specific TB T cells and correlated with the lymphocytes, while the lymphocytes also closely related to the host's anti-TB immunity and disease outcome. Hence the result of TB-IGRA could reflect the specific anti-TB immunity ability of the host, disease progression and prognosis. This study further expands the application scope of TB-IGRA technology in the diagnosis of TB and lays a foundation for clinical practice to understand the immunity state of the patients with TB and the application of auxiliary clinical immunity regulators.

Effect of compound Kushen injection on T-cell subgroups and natural killer cells in patients with locally advanced non-small-cell lung cancer treated with concomitant radiochemotherapy

ObjectiveTo observe effect of compound Kushen injection on T-cell subgroups and NK cells in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with concomitant radiochemotherapy. MethodsWe randomly divided 60 patients with locally advanced NSCLC who were treated at our hospital between May 2011 and May 2013 into a treatment group and a control group by drawing. The treatment group (n = 30) received concomitant radiochemotherapy plus compound Keshen injection, and the control group (n = 30) received only radiochemotherapy. ResultsAfter treatment, levels of CD3 +, CD4 +, CD4+/CD8 + and CD16+/CD56+ cells had significantly increased, and CD8+ cells had significantly decreased, in the treatment group compared with both their pretreatment levels and with levels in the control group. In the control group, post-treatment levels of CD3 +, CD4 +, CD4 +/CD8 + and CD16+/CD56+ cells were not significantly changed from pretreatment levels. The two groups did not significantly differ in their rates of toxicity reactions (P > 0.05). ConclusionCompound Kushen injections can increase immunologic function in patients with locally advanced non-small cell lung cancer who receive concomitant radiochemotherapy.