scholarly journals Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

Blood ◽  
2015 ◽  
Vol 125 (3) ◽  
pp. 570-580 ◽  
Author(s):  
Anne-Kathrin Hechinger ◽  
Benjamin A. H. Smith ◽  
Ryan Flynn ◽  
Kathrin Hanke ◽  
Cameron McDonald-Hyman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Chronic Gvhd ◽  
Therapeutic Activity ◽  
Cytokine Inhibition ◽  
Key Points ◽  
The Common

Key Points Monoclonal antibody blockade of the common γ chain attenuates acute and chronic GVHD. Common γ-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.

scholarly journals Immuno– enhancement effect of the Nam Dia Long decoction on immuno suppressed mice induced by cyclophosphamide

2018 ◽  
Vol 1 (6) ◽  
pp. 68-75
Author(s):  
Nuong Thi My Nguyen ◽  
Ngoc Thi Nhu Bui ◽  
Mai Tuyet Au ◽  
Hiep Minh Dinh
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Enhancement Effect ◽  
Therapeutic Activity ◽  
Immunodeficient Mice ◽  
Black Bean ◽  
Traditional Remedy ◽  
Scientific Report ◽  
Nam Dia Long

Nam Dia Long (NDL) formula which is composed of earthworm, black bean, mung bean and sweet leaf has been empirically used for the treatment of cancer, arthritis, epilepsy… However, there is no scientific report about the therapeutic activity of this traditional remedy. The aim of this work was to study on the the in vivo immunostimulating effect of NDL formula. In cyclophosphamide - induced immunodeficient mice, NDL powder at two doses of 1.2 g/kg and 2.4 g/kg attenuated the decrease of body weight, increased relatively the weights of spleen and thymus. These two doses also rised 42–44 % of leukocytes, 34 – 43 % of CD4 T cells and 35 – 46% of CD8 T cells in comparison with the pathological control. Therefore, NDL formula showed in vivo immunostimulating effect and has the potential to be developed as an adjuvant drug in cancer chemotherapy.

scholarly journals IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells

2013 ◽  
Vol 210 (3) ◽  
pp. 491-502 ◽  
Author(s):  
Shlomo Z. Ben-Sasson ◽  
Alison Hogg ◽  
Jane Hu-Li ◽  
Paul Wingfield ◽  
Xi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Interleukin 1 ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
In Vivo Models ◽  
Ifn Γ

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.

Common Gamma Chain Cytokines Contribute To Acute GvHD Via Perforin/Granzyme B-Mediated Cytotoxicity Of CD8 T Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2015-2015
Author(s):  
Vincent Schwarze ◽  
Anne-Kathrin Hechinger ◽  
Franziska Leonhardt ◽  
Gabriele Prinz ◽  
Annette Schmitt-Gräff ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
Allogeneic Transplantation ◽  
Gamma Chain ◽  
Common Gamma Chain ◽  
The Common

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an important treatment option for different hematological malignancies, but also for some nonmalignant hematological disorders such as sickle cell anemia, aplastic anemia or thalassemia(1). In the ladder group the graft-versus-leukemia (GvL) effect mediated by donor T cells is less important and prevention of graft-versus-host disease (GvHD), which occurs in 40-50% of allo-HCT patients, is a major priority. The common gamma chain (CD132) is a cytokine receptor sub-unit that is common to the interleukin (IL) receptors of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Since several of these cytokines were shown to be increased in the serum of patients developing acute GvHD, we reasoned that inhibition of CD132 could have a profound effect on acute GvHD by inhibiting the bioactivity of multiple proinflammatory cytokines. We observed that anti-CD132 treatment reduced GvHD potently with respect to survival, production of TNF, IFN-γ, IL-6, MCP-1 and GvHD histopathology. Protection was only seen when anti-CD132 was applied in a CD8 T cell-dependent GvHD model while no protection was seen when only CD4 T cells were given. Mechanistically, we could show that CD8 T cells isolated from mice treated with anti-CD132 had reduced levels of Granzyme B and that GvHD induced by Perforin-deficient T cells was resistant towards blockade by anti-CD132 treatment. These data indicated a role of the common gamma chain cytokines for the induction of Perforin/Granzyme B in CD8 T cells during GvHD. Compatible with this notion, exposure of CD8 T cells towards IL-2, IL-7, IL-15 and IL-21 alone or in combination induced increased levels of Granzyme B. Based on these findings, we concluded that CD8 T cells that are activated by common gamma chain cytokines during GvHD produce then Granzyme B which can be blocked by anti-CD132 treatment. This therapeutic approach has particular clinical potential for patients undergoing allogeneic transplantation for nonmalignant indications, since graft-versus-tumor activity is not required. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo

Blood ◽  
2013 ◽  
Vol 121 (14) ◽  
pp. 2796-2803 ◽  
Author(s):  
Suzanne M. McGoldrick ◽  
Marie E. Bleakley ◽  
Abraham Guerrero ◽  
Cameron J. Turtle ◽  
Tori N. Yamamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Cd8 T Cells ◽  
Absolute Frequency ◽  
Cord Blood Transplant ◽  
Key Points ◽  
Control Virus

Key PointsPriming of CMV-specific CD4+ and CD8+ T cells occurs as early as day 42 in patients undergoing UCBT. Lack of CMV control in UCBT patients could be related to low absolute frequency of T cells and lack of in vivo expansion of T cells.

Novel Role of Histone Deacetylase 11 (HDAC11) in Hematopoiesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4728-4728
Author(s):  
Eva Sahakian ◽  
John Powers ◽  
Pedro Horna ◽  
Jennifer Rock-Klotz ◽  
Susan Deng ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Transcriptional Activation ◽  
Effector Memory ◽  
Egfp Expression ◽  
Cell Compartment ◽  
The Common

Abstract Abstract 4728 HDAC11 is the newest member of the HDAC family. The physiological role of this HDAC was mainly unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in immune cells in-vitro1. To better elucidate the role of HDAC11 in lineage differentiation and hematopoiesis, we have utilized an HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression/transcriptional activity in immune cell compartments in vivo. Thus far, our data indicates that in hematopoietic stem cells (CD34+/Lin−), transcriptional activation of HDAC11, indicated by eGFP expression appears to be absent. Also, no eGFP expression is seen in the common lymphoid progenitors (CLP-CD34+/CD127+/CD117low/Lin−) and/or the common myeloid progenitors (CMP-CD34+/CD127−/CD117high/Lin−). In the T-cell compartment, transcriptional activation of HDAC11 increases from CD4−/CD8− T-cells to CD4+/CD8+ T-cells to single positive CD4+ and CD8+ T-cells. The expression of eGFP then decreases from naive to effector memory, but then increases again at terminal effector memory. Expression of eGFP, in the bone marrow moderately increase transitioning from Pro-B-cells (CD3−/CD200+/CD19low/CD43high), Pre-B-cells (CD3−/CD200+/CD19int/CD43int), and Immature (CD3−/CD200+/CD19high/CD43low) respectively. Interestingly eGFP expression doubles in the B-1 (CD3−/CD19+/CD200low/−) stage of differentiation in the periphery. Remarkably, eGFP expression appears to be at its highest in the plasma cell compartment of the bone marrow. A second murine model also available to us, HDAC11 knockout mice (HDAC11KO) were also utilize to confirm these findings. When compared to wild-type mice, HDAC11KO mice have increased B-1 B-cells and decreased plasma cells. In the myeloid compartment, using TgHDAC11-eGFP mice, expression of HDAC11 transcript in myeloblasts (CD34+/CD45dim/CD117+/Lin-) appears to be absent. However the expression increases to 50% in the promyelocytes (Side Scatter high/CD45dim/+/CD34−/CD117+) and to 98% in the granulocytes specifically Neutrophils (Side scatter high/CD45dim+/CD34−/CD117−/CD14−/Ly6Gbright+). Strikingly, monocytes (dendritic cells and macrophages) showed no expression of eGFP. Taken together, HDAC11 appears to be essential for proper B-cells and T-cell differentiation. It also seems to play a critical role in differentiation of granulocytes and monocytes. Therefore it is plausible that HDAC11 might function as a regulator of hematopoietic differentiation and expansion in vivo. A better understanding of this previously unknown role of HDAC11 in hematopoiesis might lead to targeted epigenetic therapies in hematological malignancies to influence the appropriate differentiation of these cells, and possibly augmenting the efficacy of immunotherapeutic approaches against malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Perforin and Granzyme B Expressed by Murine Myeloid-Derived Suppressor Cells: A Study on Their Role in Outgrowth of Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 808 ◽  
Author(s):  
Inès Dufait ◽  
Julian Pardo ◽  
David Escors ◽  
Yannick De Vlaeminck ◽  
Heng Jiang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Suppressor Cell ◽  
Melanoma Cells ◽  
B16f10 Melanoma ◽  
Knock Out ◽  
Wide Range ◽  
B16f10 Melanoma Cells

A wide-range of myeloid-derived suppressor cell (MDSC)-mediated immune suppressive functions has previously been described. Nevertheless, potential novel mechanisms by which MDSCs aid tumor progression are, in all likelihood, still unrecognized. Next to its well-known expression in natural killer cells and cytotoxic T lymphocytes (CTLs), granzyme B (GzmB) expression has been found in different cell types. In an MDSC culture model, we demonstrated perforin and GzmB expression. Furthermore, similar observations were made in MDSCs isolated from tumor-bearing mice. Even in MDSCs from humans, GzmB expression was demonstrated. Of note, B16F10 melanoma cells co-cultured with perforin/GzmB knock out mice (KO) MDSCs displayed a remarkable decrease in invasive potential. B16F10 melanoma cells co-injected with KO MDSCs, displayed a significant slower growth curve compared to tumor cells co-injected with wild type (WT) MDSCs. In vivo absence of perforin/GzmB in MDSCs resulted in a higher number of CD8+ T-cells. Despite this change in favor of CD8+ T-cell infiltration, we observed low interferon-γ (IFN-γ) and high programmed death-ligand 1 (PD-L1) expression, suggesting that other immunosuppressive mechanisms render these CD8+ T-cells dysfunctional. Taken together, our results suggest that GzmB expression in MDSCs is another means to promote tumor growth and warrants further investigation to unravel the exact underlying mechanism.

scholarly journals Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells

Blood ◽  
2013 ◽  
Vol 121 (12) ◽  
pp. 2224-2233 ◽  
Author(s):  
Ashley T. Martino ◽  
Etiena Basner-Tschakarjan ◽  
David M. Markusic ◽  
Jonathan D. Finn ◽  
Christian Hinderer ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Human Cells ◽  
Factor Ix ◽  
Cell Responses ◽  
Key Points ◽  
Cd8 Cell

Key Points A murine model was developed for capsid-specific CD8 cell responses in AAV gene therapy for hemophilia. Y-F mutant capsid minimizes the effect of anticapsid CD8+ T cells on hepatocyte-derived factor IX expression in mice and in human cells.

scholarly journals Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1450-1459 ◽  
Author(s):  
Catalina Lee-Chang ◽  
Monica Bodogai ◽  
Kanako Moritoh ◽  
Purevdorj B. Olkhanud ◽  
Andrew C. Chan ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
The Elderly ◽  
Key Points ◽  
Potential Antitumor

Key Points We report the discovery of evolutionary conserved aging-associated accumulation of 4-1BBL+ B cells that induce GrB+ CD8+ T cells. This discovery explains paradoxical retarded tumor growth in the elderly.

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