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2.
Cells ; 10(12)2021 11 25.
Article in English | MEDLINE | ID: covidwho-1542428

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.


Subject(s)
Arachidonic Acids/therapeutic use , Endocannabinoids/therapeutic use , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Lung/pathology , Polyunsaturated Alkamides/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/microbiology , Animals , Arachidonic Acids/pharmacology , Butyrates/metabolism , Cecum/pathology , Cell Separation , Colon/drug effects , Colon/pathology , Discriminant Analysis , Dysbiosis/complications , Dysbiosis/microbiology , Endocannabinoids/pharmacology , Enterotoxins , Female , Gastrointestinal Tract/drug effects , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphocyte Activation/drug effects , Mice, Inbred C57BL , Pneumonia/drug therapy , Pneumonia/microbiology , Polyunsaturated Alkamides/pharmacology , Respiratory Distress Syndrome/complications , T-Lymphocytes/drug effects
5.
Front Endocrinol (Lausanne) ; 12: 731974, 2021.
Article in English | MEDLINE | ID: covidwho-1485049

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a worldwide epidemic. It spreads very fast and hits people of all ages, especially patients with underlying diseases such as diabetes. In this review, we focus on the influences of diabetes on the outcome of SARS-CoV-2 infection and the involved mechanisms including lung dysfunction, immune disorder, abnormal expression of angiotensin-converting enzyme 2 (ACE2), overactivation of mechanistic target of rapamycin (mTOR) signaling pathway, and increased furin level. On the other hand, SARS-CoV-2 may trigger the development of diabetes. It causes the damage of pancreatic ß cells, which is probably mediated by ACE2 protein in the islets. Furthermore, SARS-CoV-2 may aggravate insulin resistance through attacking other metabolic organs. Of note, certain anti-diabetic drugs (OADs), such as peroxisome proliferator-activated receptor γ (PPARγ) activator and glucagon-like peptide 1 receptor (GLP-1R) agonist, have been shown to upregulate ACE2 in animal models, which may increase the risk of SARS-CoV-2 infection. However, Metformin, as a first-line medicine for the treatment of type 2 diabetes mellitus (T2DM), may be a potential drug benefiting diabetic patients with SARS-CoV-2 infection, probably via a suppression of mTOR signaling together with its anti-inflammatory and anti-fibrosis function in lung. Remarkably, another kind of OADs, dipeptidyl Peptidase 4 (DPP4) inhibitor, may also exert beneficial effects in this respect, probably via a prevention of SARS-CoV-2 binding to cells. Thus, it is of significant to identify appropriate OADs for the treatment of diabetes in the context of SARS-CoV-2 infections.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Lung/drug effects , Lung/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
7.
Elife ; 102021 10 12.
Article in English | MEDLINE | ID: covidwho-1464010

ABSTRACT

While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naïve and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity and altered the phenotypic properties of SARS-CoV-2-specific T cells, while in convalescents the second dose changed neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to emerging viral variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naïve counterparts.


Vaccination is one of the best ways to prevent severe COVID-19. Two doses of mRNA vaccine protect against serious illness caused by the coronavirus SARS-CoV-2. They do this, in part, by encouraging the immune system to make specialised proteins known as antibodies that recognise the virus. Most of the vaccine research so far has focussed on these antibodies, but they are only one part of the immune response. Vaccines also activate immune cells called T cells. These cells have two main roles, coordinating the immune response and killing cells infected with viruses. It is likely that they play a key role in preventing severe COVID-19. There are many kinds of T cells, each with a different role. Currently, the identity and characteristics of the T cells that protect against COVID-19 is unclear. Different types of T cells have unique proteins on their surface. Examining these proteins can reveal details about how the T cells work, which part of the virus they recognise, and which part of the body they protect. A tool called cytometry by time of flight allows researchers to measure these proteins, one cell at a time. Using this technique, Neidleman, Luo et al. investigated T cells from 11 people before vaccination and after their first and second doses. Five people had never had COVID-19 before, and six had already recovered from COVID-19. Neidleman, Luo et al. found that the T cells recognizing SARS-CoV-2 in the two groups differed. In people who had never had COVID-19 before, the second dose of vaccine improved the quality and quantity of the T cells. The same was not true for people who had already recovered from COVID-19. However, although their T cells did not improve further after a second vaccine dose, they did show signs that they might offer more protection overall. The proteins on the cells suggest that they might last longer, and that they might specifically protect the nose, throat and lungs. Neidleman, Luo et al. also found that, for both groups, T cells activated by vaccination responded in the same way to different variants of the virus. This work highlights the importance of getting both vaccine doses for people who have never had COVID-19. It also suggests that vaccination in people who have had COVID-19 may generate better T cells. Larger studies could show whether these patterns remain true across the wider population. If so, it is possible that delivering vaccines to the nose or throat could boost immunity by mimicking natural infection. This might encourage T cells to make the surface proteins that allow them to home to these areas.


Subject(s)
COVID-19 Vaccines/pharmacology , COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , Vaccines, Synthetic/pharmacology , Adult , Aged , COVID-19/prevention & control , COVID-19/virology , Female , Humans , Immunization, Secondary , Longitudinal Studies , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Young Adult
9.
Sci Adv ; 7(34)2021 08.
Article in English | MEDLINE | ID: covidwho-1365116

ABSTRACT

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.


Subject(s)
COVID-19/immunology , Immune Checkpoint Inhibitors/immunology , Melanoma/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adaptive Immunity/drug effects , Adaptive Immunity/immunology , Aged , Antibodies, Viral/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/complications , COVID-19/virology , Female , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Memory/drug effects , Immunologic Memory/immunology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Melanoma/complications , Melanoma/drug therapy , Middle Aged , Prospective Studies , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/virology
10.
Clin Immunol ; 231: 108828, 2021 10.
Article in English | MEDLINE | ID: covidwho-1363931

ABSTRACT

COVID-19 is characterized by a dysregulation of inflammatory cytokines ultimately resulting a cytokine storm that can result in significant morbidity and mortality. We developed an in-vitro assay using activated peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) or CD3 + CD28 to examine secretion of cytokines from antigen presenting cells (APCs) and T cells, respectively, in donor patients with a history of COVID-19 (convalescent) and uninfected negative controls. We hypothesized that a novel antioxidant called Tempol may decrease cytokines from activated peripheral blood cells from both COVID-19 patients and normal donors. Preincubation of immune cells with Tempol resulted in a significant (P < 0.05) decrease in multiple T cell and APC-derived cytokines from both cells of COVID-19 (n = 7) and uninfected donors (n = 7). These preliminary results suggest that Tempol has strong in-vitro anti-cytokine activity and supports additional studies examining the use of Tempol for the treatment of COVID-19.


Subject(s)
Antioxidants/pharmacology , COVID-19/immunology , Cyclic N-Oxides/pharmacology , Lymphocyte Activation/drug effects , SARS-CoV-2 , T-Lymphocytes/drug effects , Adult , Aged , Antigen-Presenting Cells/metabolism , Antigens, Viral/metabolism , Cytokines/antagonists & inhibitors , Cytokines/drug effects , Female , Humans , Male , Middle Aged , Spin Labels , T-Lymphocytes/physiology
11.
Adv Mater ; 33(40): e2102528, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1358054

ABSTRACT

Dendritic cell (DC) vaccines are used for cancer and infectious diseases, albeit with limited efficacy. Modulating the formation of DC-T-cell synapses may greatly increase their efficacy. The effects of graphene oxide (GO) nanosheets on DCs and DC-T-cell synapse formation are evaluated. In particular, size-dependent interactions are observed between GO nanosheets and DCs. GOs with diameters of >1 µm (L-GOs) demonstrate strong adherence to the DC surface, inducing cytoskeletal reorganization via the RhoA-ROCK-MLC pathway, while relatively small GOs (≈500 nm) are predominantly internalized by DCs. Furthermore, L-GO treatment enhances DC-T-cell synapse formation via cytoskeleton-dependent membrane positioning of integrin ICAM-1. L-GO acts as a "nanozipper," facilitating the aggregation of DC-T-cell clusters to produce a stable microenvironment for T cell activation. Importantly, L-GO-adjuvanted DCs promote robust cytotoxic T cell immune responses against SARS-CoV-2 spike 1, leading to >99.7% viral RNA clearance in mice infected with a clinically isolated SARS-CoV-2 strain. These findings highlight the potential value of nanomaterials as DC vaccine adjuvants for modulating DC-T-cell synapse formation and provide a basis for the development of effective COVID-19 vaccines.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Dendritic Cells/immunology , Graphite/therapeutic use , Nanostructures/therapeutic use , Adjuvants, Immunologic/chemistry , Animals , COVID-19/immunology , COVID-19 Vaccines/immunology , Dendritic Cells/drug effects , Graphite/chemistry , Humans , Mice , Nanostructures/chemistry , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
12.
Clin Res Cardiol ; 110(8): 1142-1149, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1303315

ABSTRACT

AIMS: Immunocompromised patients have been excluded from studies of SARS-CoV-2 messenger RNA vaccines. The immune response to vaccines against other infectious agents has been shown to be blunted in such patients. We aimed to analyse the humoral and cellular response to prime-boost vaccination with the BNT162b2 vaccine (Pfizer-BioNTech) in cardiothoracic transplant recipients. METHODS AND RESULTS: A total of 50 transplant patients [1-3 years post heart (42), lung (7), or heart-lung (1) transplant, mean age 55 ± 10 years] and a control group of 50 healthy staff members were included. Blood samples were analysed 21 days after the prime and the boosting dose, respectively, to quantify anti-SARS-CoV-2 spike protein (S) immunoglobulin titres (tested by Abbott, Euroimmun and RocheElecsys Immunoassays, each) and the functional inhibitory capacity of neutralizing antibodies (Genscript). To test for a specific T-cell response, heparinized whole blood was stimulated with SARS-CoV-2 specific peptides, covering domains of the viral spike, nucleocapsid and membrane protein, and the interferon-γ release was measured (QuantiFERON Monitor ELISA, Qiagen). The vast majority of transplant patients (90%) showed neither a detectable humoral nor a T-cell response three weeks after the completed two-dose BNT162b2 vaccination; these results are in sharp contrast to the robust immunogenicity seen in the control group: 98% exhibited seroconversion after the prime dose already, with a further significant increase of IgG titres after the booster dose (average > tenfold increase), a more than 90% inhibition capability of neutralizing antibodies as well as evidence of a T-cell responsiveness. CONCLUSIONS: The findings of poor immune responses to a two-dose BNT162b2 vaccination in cardiothoracic transplant patients have a significant impact for organ transplant recipients specifically and possibly for immunocompromised patients in general. It urges for a review of future vaccine strategies in these patients.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Heart Transplantation/adverse effects , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Immunogenicity, Vaccine , Immunosuppressive Agents/adverse effects , Lung Transplantation/adverse effects , Adolescent , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19 Vaccines/adverse effects , Case-Control Studies , Female , Heart-Lung Transplantation/adverse effects , Humans , Immunization Schedule , Immunocompromised Host , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Transplant Recipients , Vaccination , Young Adult
13.
Nat Rev Immunol ; 21(8): 475-484, 2021 08.
Article in English | MEDLINE | ID: covidwho-1294475

ABSTRACT

Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Humans , Immunity/drug effects , Immunity/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Treatment Outcome
14.
PLoS One ; 16(6): e0251731, 2021.
Article in English | MEDLINE | ID: covidwho-1285198

ABSTRACT

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.


Subject(s)
Hydroxychloroquine/pharmacology , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy , Programmed Cell Death 1 Receptor/immunology , Animals , Azithromycin/pharmacology , Cell Line, Tumor , Drug Antagonism , Immune Checkpoint Inhibitors/immunology , Melanoma/pathology , Mice , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
16.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1209683

ABSTRACT

The clinically indistinguishable overlap between pneumonitis caused due to immune checkpoint inhibition (ICI) and pneumonia associated with COVID-19 has posed considerable challenges for patients with cancer and oncologists alike. The cancer community continues to face the challenges that lay at the complex immunological intersection of immune-based cancer therapy and immune dysregulation that results from COVID-19. Is there compounded immune dysregulation that could lead to poor outcomes? Could ICIs, in fact, ameliorate SARS-CoV-2-driven T-cell exhaustion?A little more is known about the kinetics of the viral replication in immunocompromised patients now as compared with earlier during the pandemic. Working knowledge of the diagnostic and therapeutic nuances of SARS-CoV-2 infection in patients with active cancers, issues related to viability and replication potential of the virus, unclear role of corticosteroids among those with diminished or dysfunctional effector T-cell repertoire, and the type of immunotherapy with differential risk of pneumonitis will inform decision making related to immunotherapy choices and decision for ICI continuation in the era of COVID-19.


Subject(s)
COVID-19/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Neoplasms/therapy , Pneumonia/immunology , SARS-CoV-2/immunology , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Diagnosis, Differential , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunocompromised Host/immunology , Immunotherapy/adverse effects , Neoplasms/immunology , Pneumonia/chemically induced , Pneumonia/diagnosis , SARS-CoV-2/physiology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
17.
Front Immunol ; 12: 637651, 2021.
Article in English | MEDLINE | ID: covidwho-1154219

ABSTRACT

As COVID-19 cases continue to rise, it is imperative to learn more about antibodies and T-cells produced against the causative virus, SARS-CoV-2, in order to guide the rapid development of therapies and vaccines. While much of the current antibody and vaccine research focuses on the receptor-binding domain of S1, a less-recognized opportunity is to harness the potential benefits of the more conserved S2 subunit. Similarities between the spike proteins of both SARS-CoV-2 and HIV-1 warrant exploring S2. Possible benefits of employing S2 in therapies and vaccines include the structural conservation of S2, extant cross-reactive neutralizing antibodies in populations (due to prior exposure to common cold coronaviruses), the steric neutralization potential of antibodies against S2, and the stronger memory B-cell and T-cell responses. More research is necessary on the effect of glycans on the accessibility and stability of S2, SARS-CoV-2 mutants that may affect infectivity, the neutralization potential of antibodies produced by memory B-cells, cross-reactive T-cell responses, antibody-dependent enhancement, and antigen competition. This perspective aims to highlight the evidence for the potential advantages of using S2 as a target of therapy or vaccine design.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/therapeutic use , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibody Specificity , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Cross Reactions , Epitopes , Host-Pathogen Interactions , Humans , Immunogenicity, Vaccine , Protein Subunits , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Vaccines, Subunit/immunology , Vaccines, Subunit/therapeutic use
18.
J Physiol Pharmacol ; 71(5)2020 Oct.
Article in English | MEDLINE | ID: covidwho-1134681

ABSTRACT

In this study, the in vitro effects of 1-(4-dimethylaminobenzylidene)-2-(2-hydroxybenzylidene) hydrazone (L1) and its corresponding copper complex [Cu(L1)], synthesized in our laboratory, were investigated on the proliferative responses, Th1 (interleukin-2 (IL-2), interferon-γ (INFγ)) and Th2 (IL-4) cytokine secretion, adenosine triphosphate (ATP) levels and intracellular redox status of T lymphocytes submitted to H2O2/FeSO4-mediated oxidative stress. T cells were isolated on histopaque density gradient by differential centrifugation, and were cultured with the mitogen concanavalin A (Con A), free radical generator (H2O2/FeSO4) and with different concentrations of L1 and [Cu(L1)] (1 - 100 µM). Proliferation (MTT assay), cytokines (Elisa kits), ATP levels, cytotoxic effect (micronucleus test) and oxidative markers (glutathione, catalase, superoxide dismutase, hydroperoxide and carbonyl protein contents) were investigated after 48-h incubation. Our results showed that H2O2/FeSO4 treatment induced a reduction in T lymphocyte proliferation, cytokine secretion and ATP levels associated to an evident intracellular oxidative stress, inflammatory profile and DNA damage. Addition of L1 at 100 µM was able to increase cell proliferation, IL-2, IL-4 and INFγ secretion and ATP contents and to reduce hydroperoxide and carbonyl protein contents, catalase activity and micronuclei number in lymphocytes under oxidative stress, with a partial protection. The [Cu(L1)] exhibited protective effects in T lymphocytes by inhibiting H2O2/FeSO4 - induced cell proliferation suppression, inflammatory status, ATP loss and oxidative stress generation, whatever the concentration used. In conclusion, in the situation of excessive oxidative stress, [Cu(L1)] treatment improved T lymphocyte proliferation, cytokine production, ATP contents and oxidant/antioxidant status. [Cu(L1)] could be effective at improving oxidative stress and T cell abnormalities.


Subject(s)
Copper/pharmacology , Free Radical Scavengers/pharmacology , Hydrazines/pharmacology , Lymphocyte Activation/drug effects , T-Lymphocytes/drug effects , Cells, Cultured , Cytokines/biosynthesis , Humans , Oxidative Stress/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
19.
Sci Rep ; 11(1): 5402, 2021 03 08.
Article in English | MEDLINE | ID: covidwho-1123146

ABSTRACT

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Subject(s)
Central Nervous System/pathology , Multiple Sclerosis/immunology , T-Lymphocytes/immunology , Taurine/analogs & derivatives , Animals , Antigen Presentation/drug effects , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Cell Proliferation/drug effects , Central Nervous System/drug effects , Central Nervous System/immunology , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Myelin Proteolipid Protein/immunology , Peptide Fragments/immunology , Recurrence , Spleen/pathology , T-Lymphocytes/drug effects , Taurine/pharmacology , gamma-Aminobutyric Acid/pharmacology
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