scholarly journals Using Natural Adjuvants to Stimulate Anti-Tumour Immune Responses

2021 ◽  
Author(s):  
◽  
Sabine Kuhn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Tumour Site ◽  
Effector Cells ◽  
Draining Lymph Nodes

<p><b>The anti-tumour immune response is often not potent enough to prevent or eradicate disease. Dendritic cells (DCs) are professional antigen-presenting cells that are critical for the initiation of immune responses. While DCs frequently infiltrate tumours, lack of activation together with immuno-suppressive factors from the tumour can hamper an effective anti-tumour immune response.</b></p> <p>In this thesis, the ability of microbial stimuli and danger signals to overcome suppression and re-programme DCs and macrophages to an immuno-stimulatory phenotype was investigated. Whole live Mycobacterium smegmatis and BCG were used to provide multiple pathogen-associated molecular patterns. The intracellularly-recognised toll-like-receptor (TLR) ligands CpG and Poly IC, as well as the extracelullarly recognised TLR ligand LPS, and the danger signal monosodium-urate crystals (MSU) were also included.</p> <p>Bone-marrow derived DCs were found to respond to all adjuvants in vitro and DCs in tumour cell suspensions could be activated ex vivo. To assess the ability of adjuvants to enhance anti-tumour responses in vivo, immune-competent mice bearing established subcutaneous B16F1 melanomas were injected peri-tumorally with the different adjuvants. In line with previous reports, CpG treatment was effective in delaying tumour growth and increasing survival. A similar effect was found with Poly IC, but not with LPS, M. smegmatis, BCG or MSU alone. Combination of M. smegmatis + MSU, however, significantly delayed tumour growth and prolonged survival, while combinations of MSU + BCG or LPS were ineffective. Similar results were obtained using the B16.OVA melanoma and E.G7-OVA thymoma subcutaneous tumour models. In addition, Poly IC and MSU + M. smegmatis reduced primary tumour growth as well as lung metastases in the orthotopic 4T1 breast carcinoma model.</p> <p>Both Poly IC and MSU + M. smegmatis elicited an anti-tumour immune response that required CD8 T cells as well as NK cells. These treatments also resulted in increased proliferation of CD8 T cells and NK cells in tumour-draining lymph nodes, augmented infiltration of effector cells into the tumour, as well as enhanced production of in ammatory cytokines by effector cells and DCs in tumours. In addition, MSU + M. smegmatis also stimulated CD4 T cell proliferation, tumour-infiltrationand activation, while at the same time decreasing the frequency of regulatory T cells in tumours.</p> <p>Activation of a successful immune response to tumours was associated with early induction of IL-12 and IFNʸ, as well as moderate levels of pro-inflammatory cytokines at the tumour site and systemically. Furthermore, anti-tumour activity correlated with the induction of inflammatory monocyte-derived DCs in tumour-draining lymph nodes. These DCs were also observed in adjuvant treated tumours and their appearance was preceded by accumulation of inflammatory monocytes at the tumour site.</p> <p>These findings suggest that specific natural adjuvants can successfully modify the tumour environment and enhance the innate and adaptive anti-tumour immune response to delay tumour progression and increase survival.</p>

scholarly journals Using Natural Adjuvants to Stimulate Anti-Tumour Immune Responses

2021 ◽  
Author(s):  
◽  
Sabine Kuhn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Tumour Site ◽  
Effector Cells ◽  
Draining Lymph Nodes

<p><b>The anti-tumour immune response is often not potent enough to prevent or eradicate disease. Dendritic cells (DCs) are professional antigen-presenting cells that are critical for the initiation of immune responses. While DCs frequently infiltrate tumours, lack of activation together with immuno-suppressive factors from the tumour can hamper an effective anti-tumour immune response.</b></p> <p>In this thesis, the ability of microbial stimuli and danger signals to overcome suppression and re-programme DCs and macrophages to an immuno-stimulatory phenotype was investigated. Whole live Mycobacterium smegmatis and BCG were used to provide multiple pathogen-associated molecular patterns. The intracellularly-recognised toll-like-receptor (TLR) ligands CpG and Poly IC, as well as the extracelullarly recognised TLR ligand LPS, and the danger signal monosodium-urate crystals (MSU) were also included.</p> <p>Bone-marrow derived DCs were found to respond to all adjuvants in vitro and DCs in tumour cell suspensions could be activated ex vivo. To assess the ability of adjuvants to enhance anti-tumour responses in vivo, immune-competent mice bearing established subcutaneous B16F1 melanomas were injected peri-tumorally with the different adjuvants. In line with previous reports, CpG treatment was effective in delaying tumour growth and increasing survival. A similar effect was found with Poly IC, but not with LPS, M. smegmatis, BCG or MSU alone. Combination of M. smegmatis + MSU, however, significantly delayed tumour growth and prolonged survival, while combinations of MSU + BCG or LPS were ineffective. Similar results were obtained using the B16.OVA melanoma and E.G7-OVA thymoma subcutaneous tumour models. In addition, Poly IC and MSU + M. smegmatis reduced primary tumour growth as well as lung metastases in the orthotopic 4T1 breast carcinoma model.</p> <p>Both Poly IC and MSU + M. smegmatis elicited an anti-tumour immune response that required CD8 T cells as well as NK cells. These treatments also resulted in increased proliferation of CD8 T cells and NK cells in tumour-draining lymph nodes, augmented infiltration of effector cells into the tumour, as well as enhanced production of in ammatory cytokines by effector cells and DCs in tumours. In addition, MSU + M. smegmatis also stimulated CD4 T cell proliferation, tumour-infiltrationand activation, while at the same time decreasing the frequency of regulatory T cells in tumours.</p> <p>Activation of a successful immune response to tumours was associated with early induction of IL-12 and IFNʸ, as well as moderate levels of pro-inflammatory cytokines at the tumour site and systemically. Furthermore, anti-tumour activity correlated with the induction of inflammatory monocyte-derived DCs in tumour-draining lymph nodes. These DCs were also observed in adjuvant treated tumours and their appearance was preceded by accumulation of inflammatory monocytes at the tumour site.</p> <p>These findings suggest that specific natural adjuvants can successfully modify the tumour environment and enhance the innate and adaptive anti-tumour immune response to delay tumour progression and increase survival.</p>

scholarly journals The effect of Kefir on The Immune Response of Healthy Volunteers In Vitro

2017 ◽  
Vol 3 (2) ◽  
pp. 28
Author(s):  
Desie Dwi Wisudanti
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Fermented Milk ◽  
Bioactive Components ◽  
Ifn Γ

Kefir is a functional foodstuff of probiotics, made from fermented milk with kefir grains containing various types of beneficial bacteria and yeast. There have been many studies on the effects of oral kefir on the immune system, but few studies have shown the effect of bioactive components from kefir (peptides and exopolysaccharides/ kefiran), on immune responses. The purpose of this study was to prove the effect of kefir supernatant from milk goat on healthy immune volunteer response in vitro. The study was conducted on 15 healthy volunteers, then isolated PBMC from whole blood, then divided into 5 groups (K-, P1, P2, P3 and P4) before culture was done for 4 days. The harvested cells from culture were examined for the percentage of CD4+ T cells, CD8+ T cells, IFN-γ, IL-4 using flowsitometry and IL-2 levels, IL-10 using the ELISA method. The results obtained that kefir do not affect the percentage of CD4+ T cells and CD8+ T cells. The higher the concentration of kefir given, the higher levels of secreted IFN- γ and IL-4, but a decrease in IL-2 levels. Significant enhancement occurred at levels of IL-10 culture PBMC given kefir with various concentrations (p <0.01), especially at concentrations of 1%. These results also show the important effects of kefir bioactive components on immune responses. The conclusion of this study is that kefir can improve the immune response, through stimulation of IL-10 secretion in vitro.

scholarly journals Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging

2021 ◽  
Author(s):  
Sandip Ashok Sonar ◽  
Jennifer L Uhrlaub ◽  
Christopher P Coplen ◽  
Gregory D Sempowski ◽  
Jarrod A Dudakov ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
De Novo ◽  
Functional Decline ◽  
Lymphoid Organs ◽  
Reticular Cell ◽  
Effector Cells ◽  
Age Related ◽  
Secondary Lymphoid Organs

Secondary lymphoid organs (SLO; including the spleen and lymph nodes) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used time-stamping to indelibly mark cohorts of newly generated naive T cells (a.k.a. recent thymic emigrants - RTE) in mice, and followed their presence, phenotype and retention in SLO. We found that SLO involute asynchronously. Skin-draining lymph nodes (LN) atrophied early (6-9 months) in life and deeper tissue-draining LN and the spleen late (18-20 months), as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTE cohorts of all ages entered SLO and successfully completed post-thymic differentiation. However, in older mice, these cells were poorly retained, and those found in SLO exhibited an emigration phenotype (CCR7loS1P1hi). Transfers of adult RTE into recipients of different ages formally demonstrated that the defect segregates with the age of the SLO microenvironment and not with the age of T cells. Finally, upon intradermal immunization, RTE generated in mice as early as 6-7 months of age barely participated in de novo immune responses and failed to produce well-armed effector cells. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated and pronounced reduction of cutaneous immunity with aging.

scholarly journals Inhibition of caspase-8 activity reduces IFN-gamma expression by T cells from Leishmania major infection

2008 ◽  
Vol 80 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Wânia F. Pereira ◽  
Landi V.C. Guillermo ◽  
Flávia L. Ribeiro-Gomes ◽  
Marcela F. Lopes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Leishmania Major ◽  
Caspase 8 ◽  
Ifn Gamma ◽  
Major Infection ◽  
Draining Lymph Nodes

Following infection with Leishmania major, T cell activation and apoptosis can be detected in draining lymph nodes of C57BL/6-infected mice. We investigated the mechanisms involved in apoptosis and cytokine expression following Tcellactivation. After two weeks of infection, apoptotic T cells were not detected in draining lymph nodes but activation with anti-CD3 induced apoptosis in both CD4 and CD8 T cells. Treatment with anti-FasLigand, caspase-8 or caspase- 9 inhibitors did not block activation-induced T-cell death. We also investigated whether the blockade of caspase-8 activity would affect the expression of type-1 or type-2 cytokines. At early stages of infection, both CD4 and CD8 T cells expressed IFN-gamma upon activation. Treatment with the caspase-8 inhibitor zIETD-fmk (benzyl-oxycarbonyl-Ile- Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone) reduced the proportion of CD8 T cells and IFN-gamma expression in both CD4 and CD8T cells. We conclude that a non apoptotic role of caspase-8 activity may be required for T cell-mediated type-1 responses during L. major infection.

Dasatinib Has a Dual Mode of Action: Direct BCR-ABL1 Mediated Anti-Leukemic Effects Are Complemented by Promotion of Th1-Type and NK-Cell Mediated Cellular Immune Responses,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3760-3760 ◽  
Author(s):  
Anna Kreutzman ◽  
Jukka Vakkila ◽  
Kimmo Porkka ◽  
Satu Mustjoki
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Healthy Controls ◽  
Median Percentage ◽  
Blood Smears ◽  
Cellular Immune

Abstract Abstract 3760 Background. Tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, nilotinib) have dramatically improved outcome of CML. Besides inhibiting target kinases in leukemic cells, off-target kinases in immune effector cells are also affected. We have previously described that dasatinib therapy induces an oligoclonal expansion and mobilization of large granular lymphocytes (LGLs; CD8+ T-cells or NK-cells) in Ph+ leukemia patients. Importantly, LGL expansion is associated with improved therapy responses, but the actual mechanisms are unknown. In this study, we explored the function and anti-leukemic properties of LGLs. Methods. Peripheral blood samples from CML patients treated with dasatinib (n=10), imatinib (n=4), or nilotinib (n=7), or healthy controls (n=6) were used to analyze the activation and cytotoxicity of T- and NK-cells. Samples were collected before and after drug intake. The number of LGLs was determined from MGG stained blood smears and compared with granzyme B (GrB) positivity analyzed by flow cytometry. Th1-type cytokine (TNF-a, IFN-g) production was measured by flow cytometry after stimulation of mononuclear cells (MNCs) with a-CD3/CD28-antibodies. Unpurified and purified NK cells were cultured with K562 cells, and degranulation (CD107 analysis) and cytotoxicity were measured. Results. As GrB positivity correlated well (r=0.95, p<0.0001, n=17) with the number of LGLs counted from MGG stained blood smears, a GrB specific antibody was used to identify LGLs in further analyses. At diagnosis CML patients had more GrB+CD8+ T-cells than healthy controls (38 % vs. 11%, p=0.028). Also GrB+CD4+ T-cells were slightly increased, but did not differ significantly from healthy controls (3.6% vs. 0.8%, p=0.08). During dasatinib treatment the proportion of GrB+CD4+ (median at 6 months 28.1%, p=0.03) and GrB+CD8+ (70.9%, p=0.03) T cells increased significantly, whereas similar increase was not observed during imatinib (1.2% GrB+CD4+ and 30.0% GrB+CD8+ T-cells) or nilotinib (4.4% and 41.8%, respectively) therapies. In patients on dasatinib therapy, GrB+CD3+cells were more sensitive to CD3/CD28-antibody stimulation and a larger proportion of cells (13.7%) produced Th1-type cytokines (TNF-a+IFN-g) compared to imatinib (2.4%) or nilotinib patients (5.5%) or healthy controls (5%) under same conditions (p=0.015). As Th-1 cytokine-producing T cells are important in promoting cell-mediated immune responses, we next assessed whether dasatinib also enhances the cytolytic activity of NK cells. When MNC fraction was used as effector population (ratio 20:1), the median percentage of dead K562 cells was 18% in samples taken before dasatinib intake and 32% in samples taken 1h after dasatinib intake (p=0.004). Pre-dasatinib killing did not differ significantly from healthy volunteers (p=0.12). No increase in NK-cytotoxicity was observed after imatinib (11% vs. 8%) or nilotinib (10% vs. 10%) intake. Similar results were also obtained with purified NK-cells: the median percentage of dead K562 cells was 12% pre-dasatinib and 29% in post-dasatinib samples (p=0.06), whereas no differences were noticed with imatinib (30% vs. 28%) or nilotinib (14% vs. 15%) patients. The median percentage of dead K562 cells after incubation with pure NK-cells from healthy volunteers was 20%. Interestingly, the cytolytic ability of NK-cells differed significantly among dasatinib treated patients. When the patients were divided into two groups based on therapy response, patients who had achieved CMR within 12 months (n=4) had significantly higher cytotoxic capability compared to patients who had not (n=6): 46% vs. 28% of dead K562 cells in post-dasatinib samples (p=0.02). Conclusions. Dasatinib therapy resulted in increased numbers of GrB+ T-cells and generation of a Th1-type cellular immune response. In addition, 1h dasatinib exposure in vivo improved the cytotoxicity of NK-cells. These data support the dual mode of action of dasatinib: potent BCR-ABL1 inhibition in leukemic cells is accompanied by enhancement of cellular immunity, which likely have implications in be the long term control of Ph+ leukemia. Disclosures: Porkka: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria.

Sequential Activation of CD8+ T Cells in the Draining Lymph Nodes in Response to Pulmonary Virus Infection

2007 ◽  
Vol 179 (1) ◽  
pp. 391-399 ◽  
Author(s):  
Heesik Yoon ◽  
Kevin L. Legge ◽  
Sun-sang J. Sung ◽  
Thomas J. Braciale
Keyword(s):  
T Cells ◽  
Virus Infection ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Sequential Activation ◽  
Draining Lymph Nodes

scholarly journals High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 1112
Author(s):  
Hyung Suk Kim ◽  
Byoung Kwan Son ◽  
Mi Jung Kwon ◽  
Dong-Hoon Kim ◽  
Kyueng-Whan Min
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Survival Rate ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Specific Gene ◽  
Breast Cancer Patients ◽  
Gene Sets

Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epigenetic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze survival, genetic interaction networks and anticancer immune responses in breast cancer patients with high KDM1A expression and to explore candidate target drugs. Methods: We investigated clinicopathologic parameters, specific gene sets, immunologic relevance, pathway-based networks and in vitro drug response according to KDM1A expression in 456 and 789 breast cancer patients from the Hanyang university Guri Hospital (HYGH) and The Cancer Genome Atlas, respectively. Results: High KDM1A expression was associated with a low survival rate in patients with breast cancer. In analyses of immunologic gene sets, high KDM1A expression correlated with low immune responses. In silico flow cytometry results revealed low abundances of CD8+T cells and high programmed death-ligand 1 (PD-L1) expression in those with high KDM1A expression. High KDM1A expression was associated with a decrease in the anticancer immune response in breast cancer. In pathway-based networks, KDM1A was linked directly to pathways related to the androgen receptor signaling pathway and indirectly to the immune pathway and cell cycle. We found that alisertib effectively inhibited breast cancer cell lines with high KDM1A expression. Conclusions: Strategies utilizing KDM1A may contribute to better clinical management/research for patients with breast cancer.

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