scholarly journals The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1891
Author(s):  
Fátima Conceição-Silva ◽  
Clarissa S. M. Reis ◽  
Paula Mello De Luca ◽  
Jessica Leite-Silva ◽  
Marta A. Santiago ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Ex Vivo ◽  
Experimental Models ◽  
Formation Mechanisms ◽  
Extracellular Traps ◽  
Producer Cell ◽  
Different Populations ◽  
Development And Evolution

The first formal description of the microbicidal activity of extracellular traps (ETs) containing DNA occurred in neutrophils in 2004. Since then, ETs have been identified in different populations of cells involved in both innate and adaptive immune responses. Much of the knowledge has been obtained from in vitro or ex vivo studies; however, in vivo evaluations in experimental models and human biological materials have corroborated some of the results obtained. Two types of ETs have been described—suicidal and vital ETs, with or without the death of the producer cell. The studies showed that the same cell type may have more than one ETs formation mechanism and that different cells may have similar ETs formation mechanisms. ETs can act by controlling or promoting the mechanisms involved in the development and evolution of various infectious and non-infectious diseases, such as autoimmune, cardiovascular, thrombotic, and neoplastic diseases, among others. This review discusses the presence of ETs in neutrophils, macrophages, mast cells, eosinophils, basophils, plasmacytoid dendritic cells, and recent evidence of the presence of ETs in B lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes. Moreover, due to recently collected information, the effect of ETs on COVID-19 is also discussed.

scholarly journals Ocular Toxoplasmosis: Mechanisms of Retinal Infection and Experimental Models

Parasitologia ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 50-60
Author(s):  
Veronica Rodriguez Fernandez ◽  
Giovanni Casini ◽  
Fabrizio Bruschi
Keyword(s):  
Ex Vivo ◽  
Cell Damage ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Ocular Toxoplasmosis ◽  
Cell Infection

Ocular toxoplasmosis (OT) is caused by the parasite Toxoplasma gondii and affects many individuals throughout the world. Infection may occur through congenital or acquired routes. The parasites enter the blood circulation and reach both the retina and the retinal pigment epithelium, where they may cause cell damage and cell death. Different routes of access are used by T. gondii to reach the retina through the retinal endothelium: by transmission inside leukocytes, as free parasites through a paracellular route, or after endothelial cell infection. A main feature of OT is the induction of an important inflammatory state, and the course of infection has been shown to be influenced by the host immunogenetics. On the other hand, there is evidence that the T. gondii phenotype also has an impact on the distribution of the pathology in different areas. Although considerable knowledge has been acquired on OT, a deeper knowledge of its mechanisms is necessary to provide new, more targeted treatment strategies. In particular, in addition to in vitro and in vivo experimental models, organotypic, ex vivo retinal explants may be useful in this direction.

scholarly journals Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

2011 ◽  
Vol 4 (4) ◽  
pp. 211
Author(s):  
Serena Meraviglia ◽  
Carmela La Mendola ◽  
Valentina Orlando ◽  
Francesco Scarpa ◽  
Giuseppe Cicero ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Hematologic Malignancies ◽  
Cytolytic Activity ◽  
Cell Therapies ◽  
Stressed Cells

The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.<br />

scholarly journals High Frequency of Skin-homing Melanocyte-specific Cytotoxic T Lymphocytes in Autoimmune Vitiligo

1998 ◽  
Vol 188 (6) ◽  
pp. 1203-1208 ◽  
Author(s):  
Graham S. Ogg ◽  
P. Rod Dunbar ◽  
Pedro Romero ◽  
Ji-Li Chen ◽  
Vincenzo Cerundolo
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Ex Vivo ◽  
Hla Class I ◽  
Peripheral Tolerance ◽  
Skin Homing ◽  
Autoimmune Vitiligo ◽  
Destruction Of Melanocytes

Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. Using tetrameric complexes of human histocompatibility leukocyte antigen (HLA) class I to identify antigen-specific T cells ex vivo, we observed high frequencies of circulating MelanA-specific, A*0201-restricted cytotoxic T lymphocytes (A2–MelanA tetramer+ CTLs) in seven of nine HLA-A*0201–positive individuals with vitiligo. Isolated A2–MelanA tetramer+ CTLs were able to lyse A*0201-matched melanoma cells in vitro and their frequency ex vivo correlated with extent of disease. In contrast, no A2–MelanA tetramer+ CTL could be identified ex vivo in all four A*0201-negative vitiligo patients or five of six A*0201-positive asymptomatic controls. Finally, we observed that the A2–MelanA tetramer+ CTLs isolated from vitiligo patients expressed high levels of the skin homing receptor, cutaneous lymphocyte-associated antigen, which was absent from the CTLs seen in the single A*0201-positive normal control. These data are consistent with a role of skin-homing autoreactive melanocyte-specific CTLs in causing the destruction of melanocytes seen in autoimmune vitiligo. Lack of homing receptors on the surface of autoreactive CTLs could be a mechanism to control peripheral tolerance in vivo.

scholarly journals Four ricin chain A-based immunotoxins directed against the common chronic lymphocytic leukemia antigen: in vitro characterization

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 536-543
Author(s):  
GB Faguet ◽  
JF Agee
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Fab Fragment ◽  
In Vitro Characterization ◽  
The Common ◽  
Dose Dependent

The common B-chronic lymphocytic leukemia (B-CLL) antigen (cCLLa) appears to be ideal for targeted immunotherapy in that it is the most prevalent and disease-restricted marker in B-CLL. To assess this potential, we developed four immunotoxins (ITs) of anti-cCLLa monoclonal antibody CLL2m (an IgG2a kappa), using ricin chain A (RTA) or its deglycosylated derivative (dgA), each conjugated to either the whole IgG molecule or its Fab' fragment. Each IT was tested in vitro for specificity and cytotoxic activity (assessed by protein synthesis inhibition [PSI] and by cell kill [CK] in the clonogenic assay) against B-CLL cells. RTA-based anti-CD5 ITs and enriched normal B and T lymphocytes were used as controls. Each IT exhibited antigen-specific, dose-dependent activity. Thus, whereas B-CLL cells exhibited dose- dependent PSI and CK (whether the B-CLL clone was CD5+ or CD5-), normal B (cCLLa-/CD5-) and T lymphocytes (cCLLa-/CD5+) remained unaffected. IT potency was independent of toxin glycosylation, but was slightly influenced by antibody valence; divalent ITs were twice as potent as monovalent ITs (IC50, 2.3 v 7.1 x 10(-11) mol/L; CK, 2.6- v 2.0-log reached with 524 v 1,072 IT molecules bound/cell, respectively). In the presence of ammonium chloride or Verapamil, IT-induced CK was enhanced 10- to 80-fold. These data suggest that the cCLLa is a promising target for IT-based immunotherapy of B-CLL in vivo and ex vivo.

Absence of CCR4 Enhances the Function of Expanded Regulatory T-Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2172-2172
Author(s):  
James M. Coghill ◽  
Hans Seidel ◽  
Jonathan S. Serody
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Critical Role ◽  
Cell Transplant ◽  
Similar Frequency ◽  
Regulatory T Lymphocytes ◽  
Treg Function

Abstract Chemokine Receptor 4 (CCR4) has been shown to be important for the homing of effector T-lymphocytes (Teffs) to cutaneous and possibly pulmonary sites of inflammation. CCR4 is also expressed on the surface of regulatory T-lymphocytes (Tregs), and previous work has suggested a critical role for CCR4 for their in-vivo suppressive ability. Since the skin and lung are important sites of graft-versus-host disease (GVHD) morbidity, we set out to determine the contribution of CCR4 to both Teff and Treg function in a murine stem-cell transplant model. Methods: C57BL/6 (B6) mice served as bone marrow (BM) donors, and B6xDBA/2 F1 (B6D2) mice functioned as recipients. Teffs and Tregs were obtained from wild-type (WT) or CCR4 knockout (CCR4−/−) B6 mice. For Teff studies, recipient animals were lethally irradiated and administered T-cell depleted (TCD) BM cells +/− splenic Teffs from WT or CCR4−/− donors. For Treg studies, mice received TCD BM + WT Teffs +/− naive or expanded Tregs from WT or CCR4−/− donors. Results: Animals receiving WT or CCR4−/− Teffs all developed severe GVHD with an 88% mortality rate. Using flow cytometry, we demonstrated that WT and CCR4−/− eGFP+ Teffs were able to accumulate in the skin and lungs of recipient animals at a similar frequency, suggesting a non-essential role for CCR4 in Teff homing to these sites. Attention was next directed towards the influence of CCR4 on Treg function in-vivo. Those animals receiving BM and Teffs without Tregs developed aggressive GVHD with 100% mortality. In contrast, when animals were administered BM and naïve Tregs from either WT or CCR4−/− donors two days prior to receiving Teffs, all animals demonstrated 100% survival and only mild GVHD, suggesting a non-obligatory role for CCR4 for Treg function in-vivo. Since CCR4 is upregulated on Tregs and Teffs after activation, we next examined whether its absence would exert a greater effect on the ability of expanded Tregs to protect against GVHD in-vivo compared to naïve cells. Animals were irradiated and received TCD BM plus Teffs +/− Tregs from WT or CCR4−/− donors previously expanded in-vitro. Those animals receiving BM and Teffs without Tregs all developed severe GVHD with 100% mortality. Ex-vivo expanded WT Tregs, 80% of which expressed L-selectin at low levels, provided only marginal GVHD protection with 12.5% survival when given concurrently with Teffs at a 1:1 ratio. In contrast, expanded CCR4−/− Tregs provided superior in-vivo GVHD protection, with 50% of mice surviving long term (see figure, p=.05 for WT versus CCR4−/− Treg groups). This enhanced protection in-vivo occurred despite an inferior ability of expanded CCR4−/− Tregs to inhibit T-cell proliferation in an in-vitro mixed lymphocyte reaction compared to WT cells. Migration studies did not reveal a difference in the trafficking of expanded CCR4−/− Tregs compared to WT cells except for a greater frequency of CCR4−/− Tregs in the mesenteric lymph node on day +7. Conclusions: Our data suggest that naïve CCR4−/− Tregs are as efficient as WT cells in preventing GVHD, and that CCR4 is not required for the induction of GVHD by Teffs. Paradoxically we show that expanded Tregs function better to prevent GVHD in the absence of CCR4. Current work is underway to determine the mechanism for this finding. Figure Figure

scholarly journals Airway mechanical compression: its role in asthma pathogenesis and progression

2020 ◽  
Vol 29 (157) ◽  
pp. 190123 ◽  
Author(s):  
Punnam Chander Veerati ◽  
Jennifer A. Mitchel ◽  
Andrew T. Reid ◽  
Darryl A. Knight ◽  
Nathan W. Bartlett ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Experimental Models ◽  
Normal Lung ◽  
Mechanical Forces ◽  
Mechanical Compression ◽  
Cell Hyperplasia ◽  
Airway Narrowing ◽  
The Impact

The lung is a mechanically active organ, but uncontrolled or excessive mechanical forces disrupt normal lung function and can contribute to the development of disease. In asthma, bronchoconstriction leads to airway narrowing and airway wall buckling. A growing body of evidence suggests that pathological mechanical forces induced by airway buckling alone can perpetuate disease processes in asthma. Here, we review the data obtained from a variety of experimental models, including in vitro, ex vivo and in vivo approaches, which have been used to study the impact of mechanical forces in asthma pathogenesis. We review the evidence showing that mechanical compression alters the biological and biophysical properties of the airway epithelium, including activation of the epidermal growth factor receptor pathway, overproduction of asthma-associated mediators, goblet cell hyperplasia, and a phase transition of epithelium from a static jammed phase to a mobile unjammed phase. We also define questions regarding the impact of mechanical forces on the pathology of asthma, with a focus on known triggers of asthma exacerbations such as viral infection.

scholarly journals Lentiviral Vectors Encoding Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Receptor Genes Efficiently Convert Peripheral Blood CD8 T Lymphocytes into Cytotoxic T Lymphocytes with Potent In Vitro and In Vivo HIV-1-Specific Inhibitory Activity

2008 ◽  
Vol 82 (6) ◽  
pp. 3078-3089 ◽  
Author(s):  
Aviva Joseph ◽  
Jian Hua Zheng ◽  
Antonia Follenzi ◽  
Teresa DiLorenzo ◽  
Kaori Sango ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Ex Vivo ◽  
Lentiviral Vectors ◽  
Cell Receptor ◽  
Specific Ctls ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8+ T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) α and β chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.

scholarly journals Complementarity of clinical trials, model systems, and metabolomic workflow to unravel the healthy effects of foods: BEBESANO vs MODELSANO: A case study

2021 ◽  
Vol 2 (3) ◽  
Author(s):  
Vicente Agulló ◽  
◽  
Raúl Domínguez-Perles ◽  
Cristina García-Viguera ◽  
◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Ex Vivo ◽  
In Vitro Models ◽  
Experimental Models ◽  
Model Systems ◽  
Food Science ◽  
Clinical Models ◽  
Safe Condition

Nowadays, the health benefits associated with the consumption of plant-based food constitute a hot topic. To further demonstrate such benefits, related to antioxidant, anti-microbial, and anti-inflammatory activities, as well as the reduction of the risk of several pathophysiological conditions, the study of bioaccessibility and bioavailability of specific food’s constituents, which require interdisciplinary networks, is essential. In this frame, although different experimental models can be developed, the workflow described in the present work support the application of intervention trials in humans as the first option to study the truly effects on health of foods (e.g., plant-based foods), due to the safe condition of them and the realistic approach of this kind of studies, later explored in depth resorting to in vitro, ex vivo, and pre-clinical models, as the most appropriate workflow to get reliable results in the field of Food Science and Nutrition, regarding mechanisms of actions and molecular interactions. Thereby, the work described in the present review is developed in the frame of two consecutive and interconnected projects: BEBESANO (concluded) and MODELSANO (in process) that demonstrate the efficiency of the workflow proposed for research in the Food Science and Nutrition fields. In this regard, in the frame of BEBESANO, acute and longitudinal interventions in humans, devoted to set-up bioavailability of bioactive compounds, followed by functional studies in vivo upon pre-clinical models were conducted to unravel the relationship between bioactive compounds in plant-based beverages and the use of sweetener replacer. Now, most relevant findings from BEBESANO are being further explored in the newly granted project MODELSANO, which is aimed to uncover gaps of knowledge about the mechanisms behind the descriptive results obtained in BEBESANO, using more restrictive in vitro models (allowing the development of studies on the cellular and molecular pathways involved), and integrative cutting edge mathematical modelling alternatives. Keywords: In vivo; in vitro; bioavailability; bioaccessibility; bioactivity; health-promoting foods; metabolomic; mechanistic studies

TCR and DNAM Dependent Lysis of Acute Monocytic Leukemia (AMoL) by Vg9Vd2 T Lymphocytes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1041-1041
Author(s):  
Julie Gertner-Dardenne ◽  
Eloise Perrot ◽  
Thomas Prebet ◽  
Aude Charbonnier ◽  
Helene Sicard ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
T Lymphocytes ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Acute Myeloid

Abstract Abstract 1041 Poster Board I-63 BACKGROUNd: Compelling evidences have demonstrated the role of the immune system in the control of acute myeloid leukemia (AML). So far, T cells and natural killer (NK) cells are the major immune effectors shown to be involved in AML control. The graft-versus-leukemia (GVL) effect following allogenic stem cell transplantation as well as donor lymphocyte infusions indicate that T lymphocytes can control and eliminate AML cells. Leukemia-specific antigenic peptides have been characterized (proteinase-3 and Wilms tumor 1 protein) and serve as targets for peptide-based vaccine trials in AML. Allogenic NK cells have anti-leukemic activity as shown by killer cell inhibitory receptor (KIR)-mismatched haplo-identical stem cell transplantation. Less is known regarding the role of gd T cells in the control of AML. Recently the reconstitution of Vd1 T lymphocytes post transplantation has been shown to correlate with a better prognosis. In the present study, we have analyzed gd T cells in patients with AML and in a mouse model of human AML and focused on (Vg9) Vd2 T cells, the main subset of circulating gd T cells with anti-neoplastic activity. Human Vg9Vd2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate (BrHPP). This population may be suitable for the adoptive immunotherapy of acute myeloid leukemia (AML). However little is known about the frequency, the function and the mechanisms underlying Vg9Vd2 T-cell recognition of AML. We have focused this study on AMoL which are targets of NK and ab T cells. OBJECTIVE OF THE STUDY to describe Vg9Vd2 T cells in patients with AML and investigate their ability to induce an effective cytotoxic response against autologous AML blast in vitro and in vivo. EXPERIMENTAL PROCEDURe: We compared the phenotype and the absolute circulating Vg9Vd2 T cell levels in the blood and the bone marrow (BM) in 12 patients with AMoL (FAB AML-M4 and -M5) and 12 healthy volunteers (HV) using multi parametric flow cytometry. All patients and volunteers gave written informed consent. Vg9Vd2 T cells of AML patient were expanded ex vivo using BrHPP or Zoledronic acid plus IL2. The functions of expanded Vg9Vd2 T cells were assessed in vitro by their cytotoxicity against leukemic blasts (CD107a staining, 51Cr assay) and in vivo in immunodeficient mice transplanted with human AML cell line (U937). In these experiments, the ability of adoptively transferred Vg9Vd2 T cells to migrate into BM and improve mice survival was assessed after i.v. infusion of U937 cells into healthy female NOD-SCID, common _-chain knockout mice (NOG mice). Mice were then treated twice i.v. with 40.106 Vg9Vd2 T cells. RESULTs: Vg9Vd2 T lymphocytes are present in the blood as well as BM of AMoL patients at a lower frequency as compared to HV (median 2.07/μl vs 34/μL respectively P<0.001). Vg9Vd2 T lymphocytes from AML patients are endowed with in vitro proliferation in response to BrHPP or Zoledronic acid plus IL2 but lower than HV (fold increase median 33 versus 69, P=0.051). Expanded Vg9Vd2 express activation markers (CD69 and CCR5) and exhibit an effector/memory phenotype (CD45RA- CD27-). Their lytic potential toward autologous AML blast was equivalent to those of HV by 51Cr experiments and CD107a staining and involves the perforin-granzyme pathway. Their activity depends on both TCRVd2 and DNAX accessory molecule-1 (DNAM-1) as demonstrated by antibody blockade. In vivo data show that, upon sacrifice, Vg9Vd2 were detected in BM, spleen and blood of mice. Preliminary Kaplan-Meier analysis of pooled cohorts of Vg9Vd2-treated and untreated mice reveals that mice receiving Vg9Vd2 T cells displayed superior survival compared with untreated controls (P=0.0047). CONCLUSIOn: Altogether, our data indicate that Vg9Vd2 T cells are decreased in AML patients and have a more limited expansion potential. However, they are able to kill autologous AML blast upon stimulation in a TCRVd2 as well as the DNAM-1 receptor dependent manner. These results provide a rationale for the clinical evaluation of adoptive transfer of ex vivo expanded allogenic Vg9Vd2T cells or direct activation of Vg9Vd2T cells with IL2 + phosphoantigens in patients with AML. Disclosures: No relevant conflicts of interest to declare.

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