Proteasome Inhibitor Does Not Affect the Function of Human Immune Systems: Effects on Dendritic Cells, T Lymphocytes and NK Cells.

Abstract Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM) based on its in vitro and in vivo activity in myeloma. However, the toxicity and effects of this drug on the human immune function have not been entirely studied. In the present study, we evaluated the effects of Bortezomib on normal human immune cells including dendritic cells (DC), T lymphocytes and NK cells for cell survival, antigen expression, production of cytokines, and other key parameters of immune cell function. In our evaluation of effect of Bortezomib on DC, we did not observe significant change in the expression of cell surface antigens including CD40, CD80, CD83, CD86, HLA-ABC and HLA-DPQR molecules in terms of percentage of cells positive as well as mean fluorescence intensity (MFI). Bortezomib treated immature DC maintained the ability for antigen uptake as measured by uptake of Dextran-FITC (untrt vs. trt = 798 MFI vs. 802 MFI), maintained the expression levels of antigen uptake receptors including mannose (untrt vs. trt = 85% vs. 79%) and DEC-205 (untrt vs. trt = 49% vs. 42%), and the capacity to produce IL-12 (untrt vs. trt = 135 vs. 125 pg/ml). In addition, Bortezomib treated mature DC was able to induce comparable levels of allogenic T cell proliferation to the untreated mature DC as measured by 3[H]-Thymidine incorporation (untrt vs. trt = 212556 cpm vs. 220571 cpm). Furthermore, cell surface antigen expression including CD3, CD4, CD8, CD28, CD154 (CD40L) and TCRab on T lymphocytes were not changed by Bortezomib treatment. The treated T cells also maintained the ability to secrete IFN-g secretion in response to allogenic DC (untrt vs. trt = 85 vs. 88 pg/ml) or Staphylococcal enterotoxin B (untrt vs. trt = 131 vs. 154 pg/ml). The cytolytic activity of the NK cell population was comparable between proteasome inhibitor treated and untreated control cells against the McCAR (untrt vs. trt = 44% vs. 52%) and MM1S (49% vs. 42%) target MM cell lines. This observation was correlated with similar expression levels of CD2, CD11a, CD94, NKp30, NKp44, NKp46, and KARp50.3 activation antigens in treated versus untreated NK cells. These, in vitro results confirm lack of adverse effects of Bortezomib on immune function, and allow us to incorporate of Bortezomib in multimodality therapy that includes immunotherapy.

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Cell Transfer Therapy for Cancer: Past, Present, and Future

Journal of Immunology Research ◽

10.1155/2014/525913 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Xiaoling Qian ◽

Xian Wang ◽

Hongchuan Jin

Keyword(s):

Dendritic Cells ◽

T Lymphocytes ◽

Nk Cells ◽

Human Cancer ◽

Tumor Infiltrating Lymphocytes ◽

Cell Transfer ◽

Human Cancer Cells ◽

Cancer Tissues ◽

Infiltrating Lymphocytes

Cell transfer therapy for cancer has made a rapid progress recently and the immunotherapy has been recognized as the fourth anticancer modality after operation, chemotherapy, and radiotherapy. Lymphocytes used for cell transfer therapy include dendritic cells, natural killer (NK) cells, and T lymphocytes such as tumor-infiltrating lymphocytes (TILs) and cytotoxic T lymphocytes (CTLs). In vitro activated or engineered immune cells can traffic to cancer tissues to elicit persistent antitumor immune response which is very important especially after immunosuppressive treatments such as chemotherapy. In this review, we overviewed recent advances in the exploration of dendritic cells, NK cells, and T cells for the treatment of human cancer cells.

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Distinct cell surface ligands mediate T lymphocyte attachment and rolling on P and E selectin under physiological flow.

The Journal of Cell Biology ◽

10.1083/jcb.127.5.1485 ◽

1994 ◽

Vol 127 (5) ◽

pp. 1485-1495 ◽

Cited By ~ 99

Author(s):

R Alon ◽

H Rossiter ◽

X Wang ◽

T A Springer ◽

T S Kupper

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Cell Surface ◽

Antigen Expression ◽

Lymphocyte Antigen ◽

Selectin Ligands ◽

Distinct Cell ◽

Cutaneous Lymphocyte Antigen

Memory T lymphocytes extravasate at sites of inflammation, but the mechanisms employed by these cells to initiate contact and tethering with endothelium are incompletely understood. An important part of leukocyte extravasation is the initiation of rolling adhesions on endothelial selectins; such events have been studied in monocytes and neutrophils but not lymphocytes. In this study, the potential of T lymphocytes to adhere and roll on endothelial selectins in vitro was investigated. We demonstrate that T cells can form tethers and rolling adhesions on P selectin and E selectin under physiologic flow conditions. Tethering and rolling on P selectin was independent of cell-surface cutaneous lymphocyte antigen (CLA) expression, which correlated strictly with the capacity of T cells to form rolling adhesions under flow on E selectin. T cell tethering to P selectin was abolished by selective removal of cell surface sialomucins by a P. haemolytica O-glycoprotease, while cutaneous lymphocyte antigen expression was unaffected. A sialomucin molecule identical or closely related to P selectin glycoprotein ligand-1 (PSGL-1), the major P selectin ligand on neutrophils and HL-60 cells, appears to be a major T cell ligand for P selectin. P selectin glycoprotein ligand-1 does not appear to support T cell rolling on E selectin. In turn, E selectin ligands do not appear to be associated with sialomucins. These data demonstrate the presence of structurally distinct ligands for P or E selectins on T cells, provide evidence that both ligands can be coexpressed on a single T cell, and mediate tethering and rolling on the respective selectins in a mutually exclusive fashion.

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Dendritic cells transduced with Rsf-1/HBXAP gene generate specific cytotoxic T lymphocytes against ovarian cancer in vitro

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2010.03.038 ◽

2010 ◽

Vol 394 (3) ◽

pp. 633-638 ◽

Cited By ~ 2

Author(s):

Li Sun ◽

Beihua Kong ◽

Xiugui Sheng ◽

Jim Jinn-Chyuan Sheu ◽

Ie-Ming Shih

Keyword(s):

Ovarian Cancer ◽

Dendritic Cells ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes

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The endometrium as a source of mesenchymal stem cells in domestic animals and possible applications in veterinary medicine

Veterinaria México OA ◽

10.21753/vmoa.4.3.441 ◽

2017 ◽

Vol 4 (3) ◽

Cited By ~ 1

Author(s):

Ana G. Serrato López ◽

Juan J. Montesinos Montesinos ◽

Santiago R. Anzaldúa Arce

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Veterinary Medicine ◽

T Lymphocytes ◽

Nk Cells ◽

Domestic Animals ◽

Clinical Tool ◽

Cellular Contact ◽

Activated T Lymphocytes

Mesenchymal stem cells (MSCs) have been isolated from the endometrium of humans, mice, cows, pigs and ewes. Typically, these cells are detected in the deep regions of the endometrium, closer to the union with the myometrium. MSCs possess characteristics such as clonogenicity and multipotentiality since they can differentiate in vitro into adipogenic, chondrogenic and osteogenic lineages. These cells can be induced to differentiate in vitro not only into the mesodermal lineage but also into the endodermal and ectodermal lineages. Therefore, MSCs show a great regenerative capacity for various organs and tissues, including the endometrium. Some advantages of endometrial MSCs compared with other MSC sources are their immune modulating activity, their ease of obtainment, and the amount of sample that may be collected. The study of endometrial MSCs in domestic animals is a new and promising field because increasing our understanding of the physiology and biology of these cells may lead to a better understanding of the physiopathology of reproductive diseases, and the development of treatment methods for infertility problems. In other veterinary medicine fields, MSCs can be used for the treatment of autoimmune diseases, cardiac affections, musculoskeletal and articular lesions, muscle degeneration, type 1 diabetes, urinary tract diseases, neurodegenerative processes and tumours. Finally, MSCs are also an important clinical tool for tissue engineering and regenerative medicine. The aim of this review is to present an updated outlook of the knowledge regarding endometrial MSCs and their possible applications in veterinary medicine.Figure 1: Immunoregulatory ability of MSCs. MSCs regulate the functions of NK cells, dendritic cells (DC) and T lymphocytes. The immunosuppressive effect may occur through the secretion of different factors or through cellular contact (black arrows). The former pathway involves TGFß, HGF, IL-10, PGE2, and HLA-G5, whereas the latter pathway involves the products of IDO enzyme activity, PD-L1, HLA-G1, ICAM-I and VCAM-I. Pro-inflammatory cytokines (IFN-?) secreted by NK cells and activated T lymphocytes favour the immunoregulatory activity of MSCs (dotted lines), because they increase or induce the secretion of molecules that regulate the functions of the distinct cellular components of the immune system. Modified from Montesinos et al, and Ma et al.19,66

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Differential uptake of three clinically relevant allergens by human plasmacytoid dendritic cells

Clinical and Molecular Allergy ◽

10.1186/s12948-021-00163-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Noelle Zurmühl ◽

Anna Schmitt ◽

Ulrike Formentini ◽

Johannes Weiss ◽

Heike Appel ◽

...

Keyword(s):

Dendritic Cells ◽

Healthy Subjects ◽

Time Course ◽

In Vitro Study ◽

Allergic Diseases ◽

Plasmacytoid Dendritic Cells ◽

Antigen Uptake ◽

Der P 1 ◽

The Impact

Abstract Background Human plasmacytoid dendritic cells (pDC) have a dual role as interferon-producing and antigen-presenting cells. Their relevance for allergic diseases is controversial. and the impact of pDC on allergic immune responses is poorly understood. Methods This in vitro study on human pDC isolated from peripheral blood was designed to compare side by side the uptake of three clinically relevant representative allergens: fluorochrome-labeled house dust mite Der p 1, Bee venom extract from Apis mellifera (Api) and the food allergen OVA analyzed flow cytometry and confocal microscopy. Results We found that the internalization and its regulation by TLR9 ligation was significantly different between allergens in terms of time course and strength of uptake. Api and OVA uptake in pDC of healthy subjects was faster and reached higher levels than Der p 1 uptake. CpG ODN 2006 suppressed OVA uptake and to a lesser extent Der p 1, while Api internalization was not affected. All allergens colocalized with LAMP1 and EEA1, with Api being internalized particularly fast and reaching highest intracellular levels in pDC. Of note, we could not determine any specific differences in antigen uptake in allergic compared with healthy subjects. Conclusions To our knowledge this is the first study that directly compares uptake regulation of clinically relevant inhalative, injective and food allergens in pDC. Our findings may help to explain differences in the onset and severity of allergic reactions as well as in the efficiency of AIT.

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A hybrid of B and T lymphoblastic cell line could potentially substitute dendritic cells to efficiently expand out Her-2/neu-specific cytotoxic T lymphocytes from advanced breast cancer patients in vitro

Journal of Hematology & Oncology ◽

10.1186/s13045-017-0429-8 ◽

2017 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Sheng Chen ◽

Feifei Gu ◽

Kang Li ◽

Kai Zhang ◽

Yangyang Liu ◽

...

Keyword(s):

Breast Cancer ◽

Dendritic Cells ◽

T Lymphocytes ◽

Advanced Breast Cancer ◽

Cell Line ◽

Cancer Patients ◽

Cytotoxic T Lymphocytes ◽

Breast Cancer Patients ◽

Her 2

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Modulation of TAP-dependent antigen compartmentalization during human monocyte-to-DC differentiation

Blood Advances ◽

10.1182/bloodadvances.2018027268 ◽

2019 ◽

Vol 3 (6) ◽

pp. 839-850 ◽

Cited By ~ 2

Author(s):

Marius Döring ◽

Hanna Blees ◽

Nicole Koller ◽

Sabine Tischer-Zimmermann ◽

Mathias Müsken ◽

...

Keyword(s):

T Lymphocytes ◽

Antigen Processing ◽

Human Monocyte ◽

Antigen Uptake ◽

Adaptive Immune ◽

Histocompatibility Complex ◽

Adaptive Immune Cells ◽

Early Endosomes ◽

Secondary Lymphoid Organs

Abstract Dendritic cells (DCs) take up antigen in the periphery, migrate to secondary lymphoid organs, and present processed antigen fragments to adaptive immune cells and thus prime antigen-specific immunity. During local inflammation, recirculating monocytes are recruited from blood to the inflamed tissue, where they differentiate to macrophages and DCs. In this study, we found that monocytes showed high transporter associated with antigen processing (TAP)–dependent peptide compartmentalization and that after antigen pulsing, they were not able to efficiently stimulate antigen-specific T lymphocytes. Nevertheless, upon in vitro differentiation to monocyte-derived DCs, TAP-dependent peptide compartmentalization as well as surface major histocompatibility complex I turnover decreased and the cells efficiently restimulated T lymphocytes. Although TAP-dependent peptide compartmentalization decreased during DC differentiation, TAP expression levels increased. Furthermore, TAP relocated from early endosomes in monocytes to the endoplasmic reticulum (ER) and lysosomal compartments in DCs. Collectively, these data are compatible with the model that during monocyte-to-DC differentiation, the subcellular relocation of TAP and the regulation of its activity assure spatiotemporal separation of local antigen uptake and processing by monocytes and efficient T-lymphocyte stimulation by DCs.

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