scholarly journals The PIKfyve Inhibitor Apilimod: A Double-Edged Sword against COVID-19

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 30
Author(s):  
Maksim V. Baranov ◽  
Frans Bianchi ◽  
Geert van den Bogaart
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Host Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Good Evidence ◽  
In Vitro Studies

The PIKfyve inhibitor apilimod is currently undergoing clinical trials for treatment of COVID-19. However, although apilimod might prevent viral invasion by inhibiting host cell proteases, the same proteases are critical for antigen presentation leading to T cell activation and there is good evidence from both in vitro studies and the clinic that apilimod blocks antiviral immune responses. We therefore warn that the immunosuppression observed in many COVID-19 patients might be aggravated by apilimod.

scholarly journals Oncolytic poliovirus directs tumor antigen presentation and T cell activation in vitro

2015 ◽  
Vol 3 (S2) ◽  
Author(s):  
Michael C Brown ◽  
Eda Holl ◽  
David Boczkowski ◽  
Ross Walton ◽  
Darell D Bigner ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Tumor Antigen ◽  
Cell Activation

scholarly journals Gastric Helicobacter Infection Inhibits Development of Oral Tolerance to Food Antigens in Mice

2003 ◽  
Vol 71 (9) ◽  
pp. 5219-5224 ◽  
Author(s):  
Tamara Matysiak-Budnik ◽  
Guillaume van Niel ◽  
Francis Mégraud ◽  
Kathryn Mayo ◽  
Claudia Bevilacqua ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Oral Tolerance ◽  
Cell Activation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Agent ◽  
Dependent Manner ◽  
Food Antigens

ABSTRACT The increase in the transcellular passage of intact antigens across the digestive epithelium infected with Helicobacter pylori may interfere with the regulation of mucosal immune responses. The aim of this work was to study the capacity of Helicobacter infection to inhibit the development of oral tolerance or to promote allergic sensitization and the capacity of a gastro-protective agent, rebamipide, to interfere with these processes in mice. Oral tolerance to ovalbumin (OVA) was studied in 48 C3H/He 4-week-old mice divided into four groups: (i) OVA-sensitized mice; (ii) OVA-“tolerized” mice (that is, mice that were rendered immunologically tolerant); (iii) H. felis-infected, OVA-tolerized mice; (iv) and H. felis-infected, OVA-tolerized, rebamipide-treated mice. Oral sensitization to hen egg lysozyme (HEL) was studied in 48 mice divided into four groups: (i) controls; (ii) HEL-sensitized mice; (iii) H. felis-infected, HEL-sensitized mice; and (iv) H. felis-infected, HEL-sensitized, rebamipide-treated mice. Specific anti-OVA or anti-HEL immunoglobulin E (IgE) and IgG1/IgG2a serum titers were measured by enzyme-linked immunosorbent assay. Additionally, the capacity of rebamipide to interfere with antigen presentation and T-cell activation in vitro, as well as absorption of rebamipide across the epithelial monolayer, was tested. H. felis infection led to the inhibition of oral tolerance to OVA, but rebamipide prevented this inhibitive effect of H. felis. H. felis infection did not enhance the sensitization to HEL, but rebamipide inhibited the development of this sensitization. Moreover, rebamipide inhibited in a dose-dependent manner antigen presentation and T-cell activation in vitro and was shown to be able to cross the epithelium at a concentration capable of inducing this inhibitory effect. We conclude that H. felis can inhibit the development of oral tolerance to OVA in mice and that this inhibition is prevented by rebamipide.

scholarly journals Progesterone specifically dampens disease-associated TH1- and TH17-related immune responses during T cell activation in vitro

2020 ◽  
Author(s):  
Sandra Hellberg ◽  
Johanna Raffetseder ◽  
Olof Rundquist ◽  
Rasmus Magnusson ◽  
Georgia Papapavlou ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gene And Protein Expression ◽  
Transcriptomic Changes ◽  
Generation Sequencing ◽  
Proximity Extension Assay ◽  
Future Treatment Option

ABSTRACTThe changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induce effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4+ T cell activation, of central importance in pregnancy and disease. We found that P4 had a profound dampening effect on T cell activation, altering the gene and protein expression profile and opposing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. The TH1-and TH17-associated transcription factors STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the diseases-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12β, CXCL10 and OSM, that were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and supports its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation, suggestively through dampening of TH1 and TH17-associated immune responses and highlights the need for further studies evaluating P4 as a future treatment option.

scholarly journals In Vitro Platform Establishes Antigen-Specific CD8+ T Cell Cytotoxicity to Encapsulated Cells via Indirect Antigen Recognition

2019 ◽  
Author(s):  
Ying Li ◽  
Anthony W. Frei ◽  
Ethan Y. Yang ◽  
Irayme Labrada-Miravet ◽  
Chuqiao Sun ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Recognition ◽  
Adaptive Immune Responses ◽  
Activated T Cells ◽  
Encapsulated Cells ◽  
Adaptive Immune

AbstractCell replacement therapy has the potential to cure diseases caused by the absence or malfunction of specialized cells. A substantial impediment to the success of any non-autologous cellular transplant is the need for systemic immunosuppressive drugs to prevent host-mediated rejection of the foreign cells. Cellular encapsulation, i.e., the entrapment of cells within stable polymeric hydrogels, has been clinically explored to prevent host immune recognition and attack, but the efficacy of these encapsulated grafts is poor. While several studies have explored improvements in innate immune acceptance of these encapsulated cells, little attention has been paid to the roles of adaptive immune responses, specifically graft-targeting T cell activation, in graft destabilization. Herein, we established an efficient, single-antigen in vitro platform capable of delineating direct and indirect host T cell recognition to microencapsulated cellular grafts and evaluating their consequential impacts. Using alginate as the model hydrogel, encapsulated membrane-bound ovalbumin (mOVA) stimulator cells were incubated with antigen-specific OTI lymphocytes and subsequent OVA-specific CD8+ T cell activation and effector function were quantified. We established that alginate microencapsulation abrogates direct T cell activation by interrupting donor-host interaction; however, indirect T cell activation mediated by host antigen presenting cells (APCs) primed with shed donor antigens still occurs. These activated T cells imparted cytotoxicity on the encapsulated cells, likely via diffusion of cytotoxic solutes. Overall, this platform delivers unique mechanistic insight into the impacts of hydrogel encapsulation on host adaptive immune responses, as well as a tool for the efficient immune screening on new encapsulation methods and/or synergistic immunomodulatory agents.

scholarly journals Enhanced Dendritic Cell Maturation by TNF-α or Cytidine-Phosphate-Guanosine DNA Drives T Cell Activation In Vitro and Therapeutic Anti-Tumor Immune Responses In Vivo

2000 ◽  
Vol 165 (11) ◽  
pp. 6278-6286 ◽  
Author(s):  
Christoph Brunner ◽  
Julia Seiderer ◽  
Angelika Schlamp ◽  
Martin Bidlingmaier ◽  
Andreas Eigler ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Tnf Α

scholarly journals Induction of Antigen-Specific T-Cell Responses through Dendritic Cell Vaccination in AML: Results of a Phase I/II Trial and Ex Vivo Enhancement By Checkpoint Blockade

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 764-764 ◽  
Author(s):  
Felix S. Lichtenegger ◽  
Katrin Deiser ◽  
Maurine Rothe ◽  
Frauke M. Schnorfeil ◽  
Christina Krupka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
T Cell Activation ◽  
Cell Activation ◽  
Next Generation ◽  
Cell Responses ◽  
Ifn Γ

Abstract Postremission therapy is critical for successful elimination of minimal residual disease (MRD) in acute myeloid leukemia (AML). Innovative treatment options are needed for patients that are not eligible for allogeneic stem cell transplantation. As the intrinsic immune response against leukemia-associated antigens (LAAs) is generally low, the clinical application of checkpoint inhibitors as monotherapy is less promising in AML compared to other hemato-oncological diseases. Therapeutic vaccination with autologous dendritic cells (DCs) loaded with LAAs is a promising treatment strategy to induce anti-leukemic immune responses. We have conducted a phase I/II proof-of-concept study using monocyte-derived next-generation DCs as postremission therapy of AML patients with a non-favorable risk profile in CR/CRi after intensive induction therapy (NCT01734304). These DCs are generated using a GMP-compliant 3-day protocol including a TLR7/8 agonist, loaded with RNA encoding the LAAs WT1 and PRAME as well as CMVpp65 as adjuvant/surrogate antigen, and are applied intradermally up to 10 times within 26 weeks. The primary endpoint of the trial is feasibility and safety of the vaccination. Secondary endpoints are immunological responses and disease control. After the safety and toxicity profile was evaluated within phase I (n=6), the patient cohort was expanded to a total of 13 patients. DCs of sufficient number and quality could be generated from leukapheresis in 11/12 cases. DCs exhibited an immune-stimulatory profile based on high costimulatory molecule expression, IL-12p70 secretion, migration towards a chemokine gradient and processing and presentation of antigen. In 9/9 patients that are currently evaluable, we observed delayed-type hypersensitivity (DTH) responses at the vaccination site, but no grade III/IV toxicities. TCR repertoire analysis by next-generation sequencing revealed an enrichment of particular clonotypes at DTH sites. In the peripheral blood, we detected vaccination-specific T cell responses by multimer staining and by ELISPOT analysis: 7/7 patients showed responses to CMVpp65, including both boosting of pre-existing T cells in CMV+ patients and induction of a primary T cell response in CMV- patients. 2/7 patients exhibited responses to PRAME and WT each. 7/10 vaccinated patients are still alive, and 5/10 are in CR, with an observation period of up to 840 days. In vitro, DC-activated T cells showed an upregulation of PD-1 and LAG-3, while the DCs expressed the respective ligands PD-L1 and HLA-DR. Therefore, we studied the capacity of checkpoint blocking antibodies to further enhance T-cell activation by DCs. We found that blockade of PD-1 and particularly of LAG-3 was highly effective in enhancing both IFN-γ secretion and proliferation of T cells. Both pathways seem to target different T-cell subsets, as PD-1 blockade resulted in increased IFN-γ secretion by TN- and TEM-subsets, while blockade of LAG-3 significantly affected TN- and TCM-subsets. We conclude that vaccination with next-generation LAA-expressing DCs in AML is feasible, safe, and induces anti-leukemic immune responses in vivo. Our in vitro data supports the hypothesis that T-cell activation by means of the vaccine could be further enhanced by blocking PD-1 and/or LAG-3. Disclosures Subklewe: AMGEN Research Munich: Research Funding.

scholarly journals Maturation signatures of conventional dendritic cell subtypes in COVID-19 reflect direct viral sensing

2021 ◽  
Author(s):  
Laura Marongiu ◽  
Giulia Protti ◽  
Fabio A. Facchini ◽  
Mihai Valache ◽  
Francesca Mingozzi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Disease Severity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Main Function ◽  
Down Regulation

AbstractGrowing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19 and this negatively affects T cell activation. The presence of functional effector T cells in mild patients and dysfunctional T cells in severely ill patients suggests that adequate T cell responses are needed to limit disease severity. Therefore, understanding how cDCs cope with SARS-CoV-2 infections can help elucidate the mechanism of generation of protective immune responses. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures with the up-regulation of interferon-stimulated genes and IL-6 signaling pathways. The main difference observed between DC2s and DC3s is the up-regulation of anti-apoptotic genes in DC3s, which explains their accumulation during infection. Furthermore, comparing cDCs between severe and mild patients, we find in the former a profound down-regulation of genes encoding molecules involved in antigen presentation, such as major histocompatibility complex class II (MHCII) molecules, β2 microglobulin, TAP and costimulatory proteins, while an opposite trend is observed for proinflammatory molecules, such as complement and coagulation factors. Therefore, as the severity of the disease increases, cDC2s enhance their inflammatory properties and lose their main function, which is the antigen presentation capacity. In vitro, direct exposure of cDC2s to the virus recapitulates the type of activation observed in vivo. Our findings provide evidence that SARS-CoV-2 can interact directly with cDC2s and, by inducing the down-regulation of crucial molecules required for T cell activation, implements an efficient immune escape mechanism that correlates with disease severity.

scholarly journals Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation

2019 ◽  
Author(s):  
Rahel Frick ◽  
Lene S. Høydahl ◽  
Ina Hodnebrug ◽  
Shraddha Kumari ◽  
Grete Berntsen ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Human Antibodies ◽  
High Affinity

AbstractAntibodies specific for antigenic peptides bound to major histocompatibility complex (MHC) molecules are valuable tools for studies of antigen presentation. Such T-cell receptor (TCR)-like antibodies may also have therapeutic potential in human disease due to their ability to target disease-associated antigens with high specificity. We previously generated celiac disease (CeD) relevant TCR-like antibodies that recognize the prevalent gluten epitope DQ2.5-glia-α1a in complex with HLA-DQ2.5. Here, we report on second-generation high-affinity antibodies towards this epitope as well as a panel of novel TCR-like antibodies to another immunodominant gliadin epitope, DQ2.5-glia-α2. The strategy for affinity engineering was based on Rosetta modeling combined with pIX phage display and is applicable to similar protein engineering efforts. We isolated picomolar affinity binders and validated them in Fab and IgG format. Flow cytometry experiments with CeD biopsy material confirm the unique disease specificity of these TCR-like antibodies and reinforce the notion that B cells and plasma cells have a dominant role in gluten antigen presentation in the inflamed CeD gut. Further, the lead candidate 3.C11 potently inhibited CD4+ T-cell activation and proliferation in vitro in an HLA and epitope specific manner, pointing to a potential for targeted disease interception without compromising systemic immunity.Significance StatementConsumption of gluten-containing food drives celiac disease in genetically predisposed individuals. The underlying disease mechanism is not fully understood, but it is strictly dependent on activation of pathogenic T cells. We have engineered high-affinity human antibodies recognizing the T-cell target HLA-DQ2.5 in complex with gluten epitopes and studied cell-specific antigen presentation in patients, which shows that plasma cells and not dendritic cells dominate the inflamed tissue. The only available treatment is lifelong adherence to a gluten-free diet, which is difficult and not effective in all cases. We show that at least one of our antibodies can specifically inhibit activation of pathogenic T-cells in vitro and therefore shows promise for therapy.

scholarly journals Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Katrin Kramer ◽  
Farah Al-Barwani ◽  
Margaret A. Baird ◽  
Vivienne L. Young ◽  
David S. Larsen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mannose Receptor ◽  
Virus Like Particles ◽  
Rabbit Haemorrhagic Disease

Virus-like particles (VLP) from the rabbit haemorrhagic disease virus (RHDV) can deliver tumour antigens to induce anticancer immune responses. In this study, we explored how RHDV VLP can be functionalised to enhance the immune response by increasing antigen loading, incorporating linkers to enhance epitope processing, and targeting receptor-mediated internalisation of VLP. RHDV VLP were developed to deliver up to three copies of gp10025–33 which contained proteasome cleavable linkers to target the correct processing of the epitope. Addition of mono- and dimannosides, conjugated to the surface of the gp100 VLP, would utilise a second pathway of internalisation, mannose receptor mediated, to further augment antigen internalised by phagocytosis/macropinocytosis. In vitro cell culture studies showed that a processing linker at the C-terminus of the epitope (gp100.1LC) induced enhanced T-cell activation (7.3 ng/ml interferon- (IFN-) γ release) compared to no linker (3.0 ng/ml IFN-γ) or the linker at the N-terminus (0.8 ng/ml IFN-γ). VLP delivering two (gp100.2L) or three (gp100.3L) gp100 epitopes induced similar high T-cell activation (7.6 ng/ml IFN-γ) compared to gp100.1LC. An in vivo cytotoxicity assay and a therapeutic tumour trial confirmed that mice vaccinated with either gp100.2L or gp100.3L induced a specific antitumour immune response. Mannosylation of the gp100.2L VLP further enhanced the generated immune response, demonstrated by prolonged survival of mice vaccinated with dimannosylated gp100.2L VLP (D-gp100.2L) by 22 days compared to gp100.2L-vaccinated mice. This study showed that functionalisation of RHDV VLP by addition of an epitope-processing linker and mannosylation of the surface facilitates the efficacy of VLP as vaccination vectors for tumour immunotherapy.

scholarly journals Hyaluronan Synthesis Inhibition Impairs Antigen Presentation and Delays Transplantation Rejection

2020 ◽  
Author(s):  
Payton L. Marshall ◽  
Nadine Nagy ◽  
Gernot Kaber ◽  
Graham L. Barlow ◽  
Amrit Ramesh ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Cardiac Transplants ◽  
Transplantation Rejection ◽  
Mixed Lymphocyte Reactions

AbstractA coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition of de novo antigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.

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