Erratum: Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

Abstract Although cardiac mesenchymal cell (CMC) therapy mitigates post-infarct cardiac dysfunction, the underlying mechanisms remain unidentified. It is acknowledged that donor cells are neither appreciably retained nor meaningfully contribute to tissue regeneration—suggesting a paracrine-mediated mechanism of action. As the immune system is inextricably linked to wound healing/remodeling in the ischemically injured heart, the reparative actions of CMCs may be attributed to their immunoregulatory properties. The current study evaluated the consequences of CMC administration on post myocardial infarction (MI) immune responses in vivo and paracrine-mediated immune cell function in vitro. CMC administration preferentially elicited the recruitment of cell types associated with innate immunity (e.g., monocytes/macrophages and neutrophils). CMC paracrine signaling assays revealed enhancement in innate immune cell chemoattraction, survival, and phagocytosis, and diminished pro-inflammatory immune cell activation; data that identifies and catalogues fundamental immunomodulatory properties of CMCs, which have broad implications regarding the mechanism of action of CMCs in cardiac repair.

Download Full-text

Identification of distinct immune activation profiles in adult humans

Scientific Reports ◽

10.1038/s41598-020-77707-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Renaud Cezar ◽

Audrey Winter ◽

Delphine Desigaud ◽

Manuela Pastore ◽

Lucy Kundura ◽

...

Keyword(s):

T Cells ◽

Immune Activation ◽

Cell Activation ◽

Immune Cell ◽

Nk Cell ◽

Liver Steatosis ◽

Treg Cells ◽

Microbial Translocation ◽

Color Flow

AbstractLatent infectious agents, microbial translocation, some metabolites and immune cell subpopulations, as well as senescence modulate the level and quality of activation of our immune system. Here, we tested whether various in vivo immune activation profiles may be distinguished in a general population. We measured 43 markers of immune activation by 8-color flow cytometry and ELISA in 150 adults, and performed a double hierarchical clustering of biomarkers and volunteers. We identified five different immune activation profiles. Profile 1 had a high proportion of naïve T cells. By contrast, Profiles 2 and 3 had an elevated percentage of terminally differentiated and of senescent CD4+ T cells and CD8+ T cells, respectively. The fourth profile was characterized by NK cell activation, and the last profile, Profile 5, by a high proportion of monocytes. In search for etiologic factors that could determine these profiles, we observed a high frequency of naïve Treg cells in Profile 1, contrasting with a tendency to a low percentage of Treg cells in Profiles 2 and 3. Moreover, Profile 5 tended to have a high level of 16s ribosomal DNA, a direct marker of microbial translocation. These data are compatible with a model in which specific causes, as the frequency of Treg or the level of microbial translocation, shape specific profiles of immune activation. It will be of interest to analyze whether some of these profiles drive preferentially some morbidities known to be fueled by immune activation, as insulin resistance, atherothrombosis or liver steatosis.

Download Full-text

IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

Neuro-Oncology ◽

10.1093/neuonc/noz175.538 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi129-vi129

Author(s):

Marilin Koch ◽

Mykola Zdioruk ◽

M Oskar Nowicki ◽

Estuardo Aguilar ◽

Laura Aguilar ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Immune Cell ◽

Symptomatic Treatment ◽

Tumor Cell Death ◽

The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

Download Full-text

Suppression of NK Cell-Mediated Bone Marrow Cell Rejection by CD4+CD25+ Regulatory T Cells: Linkage of Adaptive to Innate Responses.

Blood ◽

10.1182/blood.v106.11.2195.2195 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2195-2195

Author(s):

William J. Murphy ◽

Isabel Bareo ◽

Alan M. Hanash ◽

Lisbeth A. Welniak ◽

Kai Sun ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Regulatory T Cells ◽

Cell Function ◽

Nk Cell ◽

Marrow Cell ◽

Poly I:C ◽

Hybrid Resistance

Abstract While a link between the innate to adaptive immune system has been established, studies demonstrating direct effects of T cells in regulating Natural Killer (NK) cell function have been lacking. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to potently inhibit adaptive responses by T cells. We therefore investigated whether Tregs could affect NK cell function in vivo. Using a bone marrow transplantation (BMT) model of hybrid resistance, in which parental (H2d) marrow grafts are rejected by the NK cells of the F1 recipients (H2bxd), we demonstrate that the in vivo removal of host Tregs significantly enhances NK-cell mediated BM rejection. This heightened rejection was mediated by the specific NK cell Ly-49+ subset previously demonstrated to reject the BMC in this donor/host pairing. The depletion of Tregs could also further increase rejection already enhanced by treating recipients with the NK cell activator, poly I:C. Although splenic NK cell numbers were not significantly altered, increased splenic NK in vitro cytotoxic activity was observed from the recovered cells. The regulatory role of Tregs was confirmed in adoptive transfer studies in which transferred CD4+CD25+ Tregs resulted in abrogation of NK cell-mediated hybrid resistance. Thus, Tregs can potently inhibit NK cell function in vivo and their depletion may have therapeutic ramifications with NK cell function in BMT and cancer therapy.

Download Full-text

Mononuclear myeloid-derived “suppressor” cells express RAE-1 and activate natural killer cells

Blood ◽

10.1182/blood-2008-03-143776 ◽

2008 ◽

Vol 112 (10) ◽

pp. 4080-4089 ◽

Cited By ~ 99

Author(s):

Norman Nausch ◽

Ioanna E. Galani ◽

Eva Schlecker ◽

Adelheid Cerwenka

Keyword(s):

Nk Cells ◽

Natural Killer ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Nk Cell ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing

Abstract Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice and potently suppress T-cell activation. In this study, we investigated whether MDSCs regu-late natural killer (NK)–cell function. We discovered that mononuclear Gr-1+CD11b+F4/80+ MDSCs isolated from RMA-S tumor-bearing mice do not suppress, but activate NK cells to produce high amounts of IFN-γ. Gr-1+CD11b+F4/80+ MDSCs isolated from tumor-bearing mice, but not myeloid cells from naive mice, expressed the ligand for the activating receptor NKG2D, RAE-1. NK-cell activation by MDSCs depended partially on the interaction of NKG2D on NK cells with RAE-1 on MDSCs. NK cells eliminated Gr-1+CD11b+F4/80+ MDSCs in vitro and upon adoptive transfer in vivo. Finally, depletion of Gr-1+ cells that comprise MDSCs confirmed their protective role against the NK-sensitive RMA-S lymphoma in vivo. Our study reveals that MDSCs do not suppress all aspects of antitumor immune responses and defines a novel, unexpected activating role of MDSCs on NK cells. Thus, our results have great impact on the design of immune therapies against cancer aiming at the manipulation of MDSCs.

Download Full-text

Regulation of Immunity via Multipotent Mesenchymal Stromal Cells

Acta Naturae ◽

10.32607/20758251-2012-4-1-23-31 ◽

2012 ◽

Vol 4 (1) ◽

pp. 23-31 ◽

Cited By ~ 9

Author(s):

Yu. P. Rubtsov ◽

Yu. G. Suzdaltseva ◽

K. V. Goryunov ◽

N. I. Kalinina ◽

V. Yu. Sysoeva ◽

...

Keyword(s):

Autoimmune Diseases ◽

Mesenchymal Stromal Cells ◽

Immune Cells ◽

Stromal Cells ◽

Cell Activation ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Nk Cell ◽

Multipotent Mesenchymal Stromal Cells

Immune cells responsible for inflammation development are involved in tissue damage caused by wounding and various pathologies. Control of immune cell activation could be of significant benefit for regenerative medicine and the treatment of patients with autoimmune and degenerative diseases. It is a proven fact that MCSs (multipotent mesenchymal stromal cells) are capable of suppressing immune responses via the inhibition of dendritic cell maturation and via the restraining of the T, B, and NK cell function in the course of autoimmune diseases and various forms of inflammation. MSCs can be isolated easily from almost every type of tissue or organ and subsequently expanded in vitro. These cells are self-renewable and can be differentiated into various cell types of mesenchymal lineage. The current review contains a collection and critical analysis of data regarding the molecular mechanisms responsible for cross-talk between immune cells and MSCs. Some of these mechanisms can be used for the development of new practical approaches for the treatment of autoimmune diseases.

Download Full-text