scholarly journals Electroacupuncture at Bilateral Zusanli Points (ST36) Protects Intestinal Mucosal Immune Barrier in Sepsis

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mei-fei Zhu ◽  
Xi Xing ◽  
Shu Lei ◽  
Jian-nong Wu ◽  
Ling-cong Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
High Frequency ◽  
Low Frequency ◽  
Intestinal Injury ◽  
High Morbidity ◽  
Protective Effects ◽  
High Permeability ◽  
Injury Index ◽  
Underlying Mechanisms

Sepsis results in high morbidity and mortality. Immunomodulation strategies could be an adjunctive therapy to treat sepsis. Acupuncture has also been used widely for many years in China to treat sepsis. However, the underlying mechanisms are not well-defined. We demonstrated here that EA preconditioning at ST36 obviously ameliorated CLP-induced intestinal injury and high permeability and reduced the mortality of CLP-induced sepsis rats. Moreover, electroacupuncture (EA) pretreatment exerted protective effects on intestinal mucosal immune barrier by increasing the concentration of sIgA and the percentage of CD3+,γ/δ, and CD4+ T cells and the ratio of CD4+/CD8+ T cells. Although EA at ST36 treatments immediately after closing the abdomen in the CLP procedure with low-frequency or high-frequency could not reduce the mortality of CLP-induced sepsis in rats, these EA treatments could also significantly improve intestinal injury index in rats with sepsis and obviously protected intestinal mucosal immune barrier. In conclusion, our findings demonstrated that EA at ST36 could improve intestinal mucosal immune barrier in sepsis induced by CLP, while the precise mechanism underlying the effects needs to be further elucidated.

scholarly journals Frequent Recurrences of Genital Herpes Are Associated with Enhanced Systemic HSV-Specific T Cell Response

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Michal Holub ◽  
Alžběta Stráníková ◽  
Pavel Chalupa ◽  
Simona Arientová ◽  
Kateřina Roubalová ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Genital Herpes ◽  
Cd8 T Cells ◽  
High Frequency ◽  
Low Frequency ◽  
T Cell Responses ◽  
Healthy Controls ◽  
Cell Responses ◽  
Hla Dr

Objectives. Genital herpes simplex virus (HSV) infection is controlled by HSV-specific T cells in the genital tract, and the role of systemic T cell responses is not fully understood. Thus, we analysed T cell responses in patients with recurrent genital herpes (GH). Methods. T cell responses to HSV-1 and HSV-2 native antigens and the expression of HLA-DR and CD38 molecules on circulating CD8+ T cells were analysed in adults with high frequency of GH recurrences (19 patients) and low frequency of GH recurrences (7 patients) and 12 HSV-2 seronegative healthy controls. The study utilized the interferon-γ Elispot assay for measurement of spot-forming cells (SFC) after ex vivo stimulation with HSV antigens and flow cytometry for analysis of the expression of activation markers in unstimulated T cells. Results. The patients with high frequency of GH recurrences (mean number of recurrences of 13.3 per year) had significantly enhanced HSV-specific T cell responses than the HSV-2 seronegative healthy controls. Moreover, a trend of higher numbers of SFC was observed in these patients when compared with those with low frequency of GH recurrences (mean number of recurrences of 3.3 per year). Additionally, no differences in CD38 and HLA-DR expression on circulating CD8+ T cells were found among the study groups. Conclusions. Frequency of GH recurrences positively correlates with high numbers of systemic HSV-specific T cells.

scholarly journals High frequency of circulating HBcAg-specific CD8 T cells in hepatitis B infection: a flow cytometric analysis

2001 ◽  
Vol 124 (3) ◽  
pp. 435-444 ◽  
Author(s):  
S. Matsumura ◽  
K. Yamamoto ◽  
N. Shimada ◽  
N. Okano ◽  
R. Okamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis B ◽  
Cd8 T Cells ◽  
High Frequency ◽  
Flow Cytometric Analysis ◽  
Hepatitis B Infection ◽  
Flow Cytometric

scholarly journals Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Dong Chen ◽  
Zhiliang Duan ◽  
Wenhua Zhou ◽  
Weiwei Zou ◽  
Shengwei Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Cd8 T Cells ◽  
Zika Virus ◽  
Encephalitis Virus ◽  
Protective Effects ◽  
Zikv Infection ◽  
Lethal Effects

Cross-reactive anti-flaviviral immunity can influence the outcome of infections with heterologous flaviviruses. However, it is unclear how the interplay between cross-reactive antibodies and T cells tilts the balance toward pathogenesis versus protection during secondary Zika virus (ZIKV) and Japanese encephalitis virus (JEV) infections. We show that sera and IgG from JEV-vaccinated humans and JEV-inoculated mice cross-reacted with ZIKV, exacerbated lethal ZIKV infection upon transfer to mice, and promoted viral replication and mortality upon ZIKV infection of the neonates born to immune mothers. In contrast, transfer of CD8+ T cells from JEV-exposed mice was protective, reducing the viral burden and mortality of ZIKV-infected mice and abrogating the lethal effects of antibody-mediated enhancement of ZIKV infection in mice. Conversely, cross-reactive anti-ZIKV antibodies or CD8+ T cells displayed the same pathogenic or protective effects upon JEV infection, with the exception that maternally acquired anti-ZIKV antibodies had no effect on JEV infection of the neonates. These results provide clues for developing safe anti-JEV/ZIKV vaccines.

Stromal Cells Protect B-CLL Cells from Killing by Antigen-Specific Cytotoxic T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2814-2814
Author(s):  
Katja Zirlik ◽  
Meike Burger ◽  
Philipp Brantner ◽  
Gabriele Prinz ◽  
Maike Buchner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cytotoxic T Cells ◽  
Protective Effects ◽  
Stromal Cell Line

Abstract B-cell malignancy-derived immunoglobulin (idiotype) and survivin, a member of the inhibitor of apoptosis gene family and a shared tumor-associated antigen, are expressed by B-CLL cells. Idiotype- and survivin-specific cytotoxic T cells (CTLs), capable of lysing primary autologous B-CLL cells, can be induced in patients with B-CLL. However, the leukemia cell microenvironment was shown to protect B-CLL cells from apoptosis. The protective effects of stromal cells can be reversed by CXCR4 antagonists in vitro and resensitize CLL cells to spontaneous and chemotherapy-induced apoptosis. The aim of the present study is to investigate whether stromal cell contact impairs CLL killing by CTLs raised against immunoglobulin- or survivin-derived peptides and whether the addition of CXCR4 inhibitors enhances T cell mediated cytotoxicity. To analyze the T cell response, we isolated CD8+ T cells and PBMCs from HLA-A2+ healthy donors. PBMCs were differentiated into dendritic cells (DCs) and CD40-activated B cells. CD8+ T cells were primarily stimulated with peptide-pulsed DCs and then restimulated weekly with peptide-pulsed CD40-activated B cells. Heteroclitic framework region (FR−), heteroclitic complementarity-determining region (CD−) derived peptides, and native and heteroclitic survivin-derived peptides were used for CTL induction. As expected, heteroclitic peptide modifications increased the binding affinity to HLA-A*0201 compared to the native peptide as predicted by the Parker Score (Median change of predicted half-time of dissociation to HLA class I molecules 1429 minutes) and measured by the T2 binding assay (Fluorescence Index (FI) native 0.2; FI heteroclitic 0.9). Cytotoxicity of T cells was assessed by chromium release assay and by flow cytometry against CFSE-labelled CLL cells alone and in co-culture with unlabelled stromal cells in the absence or presence of CXCR4 blocking agents. The induced CTLs efficiently lysed allogenic HLA-A2+ CLL cells (mean cytotoxicity at 30:1, 10:1, 3:1 effector-to-target (E:T) ratio: 15,5%+/−2,8; 7,5%+/−2,8; and 1,9%+/− 0,6), but not HLA-A2 negative CLL cells. Co-culture of CLL cells with the murine stromal cell line M2-10B4 resulted in protection of CLL cells from lysis by antigen-specific cytotoxic T cells in vitro, indeed suggesting a protective role of the microenvironment (mean cytotoxicity at 30:1, 10:1, 3:1 E:T ratio: 5,2%+/−4,1; 0,4%+/−1,6; 1,2%+/−2,0). In contrast to apoptosis induced by fludarabine, CXCR4 blocking agents did not reverse the protective effects of the stromal cell line on T cell mediated cytotoxicity (mean cytotoxicity 30:1, 10:1, 3:1 E:T ratio: 3,1%+/−2,4; 0,8%+/−2,5; 2,3%+/−1,6). These data indicate that the microenvironment may exert protective effects against immunotherapeutic strategies in CLL. However, the protective interaction is not entirely mediated by the CXCR4 - CXCL12 axis. Additional cell-cell interactions appear to play a role and need to be identified as therapeutic targets in order to effectively interrupt the protective effect of the microenvironment on T cell mediated cytotoxicity of B-CLL cells.

Vaccination with survivin and PSMA-derived peptides for controlling biochemical recurrence in prostate cancer: A pilot study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16042-e16042
Author(s):  
R. Valdagni ◽  
A. Marrari ◽  
P. Squarcina ◽  
S. Villa ◽  
P. Filipazzi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Pilot Study ◽  
Cd8 T Cells ◽  
Biochemical Recurrence ◽  
Tumor Vaccine ◽  
Low Frequency ◽  
Cross Reactivity ◽  
Treg Frequency ◽  
Priming Phase

e16042 Background: A significant percentage of patients (pts) progress after first line treatment of prostate cancer (PCa). We present preliminary results of pilot study using a multiple peptide-based anti-tumor vaccine. Methods: A phase I-II trial of vaccination (vax) with HLA-A*0201-restricted peptides from PSMA and Survivin was carried out in 20 pts with b-failure after surgery or radiotherapy (mean pre-vax PSA: 1.83 ng/ml). Vax consisted of two peptides from PSMA (PSMA4–12 and PSMA711–719) and one from Survivin (SVV96–104/97M) given by 4 fortnightly (priming) and 4 monthly administrations (boosting). To selectively eliminate regulatory T cells (Treg) and possibly enhance immunization, peptides were preceded by low dose cyclophosphamide (CTX, 300 mg/mq, i.v.). Antigen (Ag) and tumor-specific T cell responses were extensively monitored in peripheral blood together with CD4+CD25+Foxp3+ Treg frequency. PSA trend was also registered. Results: Vax was well tolerated. Most pts (19/20) showed a significant increase of SVV96–104/97M-specific T cells (mean 14 in pre-vax vs 170 in post-vax PBMC), while response to PSMA was achieved in about half of the pts and only to PSMA711–719 peptide (mean 12 in pre-vax vs 86 in post-vax PBMC). Increments of HLA-A*0201/SVV96–104/97M or PSMA711–719 multimer+ CD8+ T cells were induced in 50 and 35% pts, respectively. Vax-induced Ag-specific T cells displayed however limited cross-reactivity with HLA-A*0201+ PCa cells. No effect of CTX on Treg frequency was observed. 6 pts had no biochemical response to vax and switched to hormonal therapy, while 14/20 exhibited a significant although transient PSA decrease during vax (11 in the priming phase and 3 in boosting). Conclusions: Peptide vax could rapidly enhance Ag-specific immune responses in most treated pts. However, the reduced ability of vax-induced Ag-specific CD8+ T cells to cross-recognize PCa cells, together with their low frequency in PBMC, could explain why PSA control was achieved only transiently and in strict dependence with vax administration. Anti- tumor vax represent a useful tool for controlling PCa biochemical recurrence in the absence of major side effects, but immunization protocols inducing efficient tumor cell killing still need to be identified. No significant financial relationships to disclose.

scholarly journals Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1537-1544 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Laura A. Johnson ◽  
Bianca Heemskerk ◽  
John R. Wunderlich ◽  
Mark E. Dudley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Cd8 T Cells ◽  
Tumor Antigen ◽  
Ki 67 ◽  
Normal Tissues ◽  
Functionally Impaired ◽  
Underlying Mechanisms

Abstract Tumor antigen–specific T cells are found within melanomas, yet tumors continue to grow. Although the tumor microenvironment is thought to influence the suppression of tumor-reactive T cells, the underlying mechanisms for this T-cell dysfunction are not clear. Here, we report that the majority of tumor infiltrating T lymphocytes (TIL), including MART-1/Melan-A melanoma antigen–specific CD8 T cells, predominantly expressed PD-1, in contrast to T cells in normal tissues and peripheral blood T lymphocytes (PBL). PD-1+ TIL expressed CTLA-4 and Ki-67, markers that were not expressed by PD-1− TIL and T cells in the normal tissues and PBL. Moreover, PD-1+ TIL were primarily HLA-DR+ and CD127−, in contrast to PD-1− TIL. Effector cytokine production by PD-1+ TIL was impaired compared with PD-1− TIL and PBL. Collectively, the phenotypic and functional characterizations of TIL revealed a significantly higher frequency and level of PD-1 expression on TIL compared with normal tissue T-cell infiltrates and PBL, and PD-1 expression correlated with an exhausted phenotype and impaired effector function. These findings suggest that the tumor microenvironment can lead to up-regulation of PD-1 on tumor-reactive T cells and contribute to impaired antitumor immune responses.

The molecular and immune characteristics, antitumor activity of crizotinib in non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping alterations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20588-e20588
Author(s):  
Jiadi Gan ◽  
Wenfeng Fang ◽  
Weineng Feng ◽  
Jiexia Zhang ◽  
Huojin Deng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Antitumor Activity ◽  
High Frequency ◽  
Low Frequency ◽  
Small Cell ◽  
Splice Sites ◽  
Small Cell Lung ◽  
Tumor Region ◽  
Nsclc Patients

e20588 Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P< 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.

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