#Nk Cells

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The anti-diabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of anti-apoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.
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Adenosine receptor 2a agonists target mouse CD11cT-bet B cells in infection and autoimmunity

CD11c+T-bet+ B cells are recognized as an important component of humoral immunity and autoimmunity. These cells can be distinguished from other B cells by their higher expression of the adenosine receptor 2a. Here we address whether A2A receptor activation can affect CD11c+T-bet+ B cells. We show that administration of the A2A receptor agonist CGS-21680 depletes established CD11c+T-bet+ B cells in ehrlichial-infected mice, in a B cell-intrinsic manner. Agonist treatment similarly depletes CD11c+T-bet+ B cells and CD138+ B cells and reduces anti-nuclear antibodies in lupus-prone mice. Agonist treatment is also associated with reduced kidney pathology and lymphadenopathy. Moreover, A2A receptor stimulation depletes pathogenic lymphocytes and ameliorates disease even after disease onset, highlighting the therapeutic potential of this treatment. This study suggests that targeting the adenosine signaling pathway may provide a method for the treatment of lupus and other autoimmune diseases mediated by T-bet+ B cells.
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Shares Of Gamida Cell (GMDA) Were Inclining In Premarket? Why Did It Happen?

Gamida Cell Ltd. (GMDA) shares were rising 13.51% to trade at $2.52 in pre-market at last check. GMDA stock lost -2.20% to close Tuesday’s session at $2.22. The volume of GMDA stock remained 0.35 million shares, which was lower than the average daily volume of 0.63 million shares within the past 50 days. Gamida Cell shares have fallen by -77.44% over the last 12 months, and they have moved down by -1.77% in the past week.
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Here is why ImmunityBio Inc. (IBRX) stock soared in the after-hours on Tuesday?

ImmunityBio Inc. (IBRX) shares soared 11.47% in after-hours on Tuesday, January 18, 2022, and closed at $6.90. However, in the regular trading sessions of Tuesday, IBRX’s stock lost 7.20%. IBRX shares have fallen 66.25% over the last 12 months, and they have moved up 0.81% in the past week. Over the past three months, the stock has lost 30.68%, while over the past six months, it has declined 45.65%.

NK cell dysfunction in patients with COVID-19

Cellular & Molecular Immunology (2022)Cite this article. A substantial proportion of patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might develop severe pneumonia and fibrotic lung damage at later stages after the infection. Efficient antiviral immunity and prevention of fibrosis progression are critical for COVID-19 control. Natural killer (NK) cells, whose targeting strategies have already provided therapeutic benefits in immunotherapy against tumors, are innate lymphocytes that also play an important role in antiviral immunity. In support of targeting NK cells in patients with COVID-19, Krämer et al. recently provided evidence that NK cells display anti-SARS-CoV-2 activity [1]. They showed that purified peripheral NK cells from healthy individuals reduce viral protein levels in cocultured SARS-CoV-2-infected cells. The effector cytokines IFN-γ and TNF-α produced by NK cells are essential for this process. In addition to antiviral activity, NK cells also function to limit tissue fibrosis [2]. Krämer et al. showed that IL-2-activated NK cells from control individuals reduce the expression of the profibrotic marker genes COL1A1 and ACTA2 in human lung fibroblasts, suggesting that NK cells might normally possess antifibrotic activity in the lung. Based on these data, the normal activity of NK cells might improve the control of COVID-19 by suppressing the virus and inhibiting fibrosis progression.

The frequencies of peripheral blood CD5(+)CD19(+) B cells, CD3(-)CD16(+)CD56(+) NK, and CD3(+)CD56(+) NKT cells and serum interleukin-10 in patients with multiple sclerosis and neuromyelitis optica spectrum disorder

Allergy Asthma Clin Immunol. 2022 Jan 14;18(1):5. doi: 10.1186/s13223-021-00596-5. BACKGROUND: Multiple sclerosis (MS) and neuromyelitis optica syndrome disease (NMOSD) are inflammatory diseases of the central nervous system. The pathogenesis and treatments for these two conditions are very different. Natural killer (NK) and natural killer T (NKT) cells are immune cells with an important role in shaping the immune response. B cells are involved in antigen presentation as well as antibody and cytokine production. There is conflicting evidence of the roles of NK, NKT, and B cells in the two conditions. We aimed to compare the frequency of CD3–CD16+CD56+NK, CD3+ CD56+ NKT, and CD5+CD19+ B cells in the peripheral blood and serum Interleukin-10 (IL-10) in patients with MS and NMOSD.
BioMed Central

Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression

Genome Biology volume 23, Article number: 24 (2022) Cite this article. Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks.

Natural Killer Cell-Associated Markers Investigated in Gastric Cancer

Image: Advanced stage of stomach cancer with stomach tissue array, including pathology grade, malignant tumors (TNM) and clinical stage (Photo courtesy of SuperBioChips Laboratories) Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Although the survival rates of GC patients have increased with proper screening systems,...

Researchers develop new generation tumor-specific pro-IL-12

Interleukin-12 (IL-12), a potent inducer of cell-mediated immunity, can stimulate the anti-tumor effector functions of the activated T and NK cells for solid tumors rejection. However, clinical administration of IL-12 has been limited because of its short half-life, low efficacy, and dose-limiting systemic toxicity. In a study published in Science...

Latency reversal plus natural killer cells diminish HIV reservoir in vivo

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.

Mapping regulatory T-cell populations in COVID-19 patients

In a recent study published on the medRxiv* preprint server, researchers used mass spectrometry to investigate changes to immune systems, in particular regulatory T-cells (Tregs), in a large cohort of moderate, severe, and critical Japanese coronavirus disease 2019 (COVID-19) patients and healthy controls. Tregs are a complex population of immune...

Imaging α-GalCer–Activated iNKT Cells in a Hepatic Metastatic Environment

Patients with colorectal cancer frequently develop liver metastases after, and perhaps as a consequence of, lifesaving surgical resection of the primary tumor. This creates a potential opportunity for prophylactic metastatic treatment with novel immunostimulatory molecules. Here, we used state-of-the-art intravital imaging of an experimental liver metastasis model to visualize the early behavior and function of invariant natural killer T (iNKT) cells stimulated with α-galactosylceramide (α-GalCer). Intravenous α-GalCer prior to tumor cell seeding in the liver significantly inhibited tumor growth. However, some seeding tumor cells survived. A multiple dosing regimen reduced tumor burden and prolonged the life of mice, whereas tumors returned within 5 days after a single dose of α-GalCer. With multiple doses of α-GalCer, iNKT cells increased in number and granularity (as did NK cells). As a result, the total number of contacts and time in contact with tumors increased substantially. In the absence of iNKT cells, the beneficial effect of α-GalCer was lost. Robust cytokine production dissipated over time. Repeated therapy, even after cytokine dissipation, led to reduced tumor burden and prolonged survival. Serial transplantation of tumors exposed to α-GalCer–activated iNKT cells did not induce greater resistance, suggesting no obvious epigenetic or genetic immunoediting in tumors exposed to activated iNKT cells. Very few tumor cells expressed CD1d in this model, and as such, adding monomers of CD1d–α-GalCer further reduced tumor growth. The data suggest early and repeated stimulation of iNKT cells with α-GalCer could have direct therapeutic benefit for patients with colorectal cancer who develop metastatic liver disease.

Selenium Deficiency Linked to Severe COVID-19: how to get enough Selenoproteins

Selenium deficiency was found in 42% of hospitalized COVID-19 patients, and Selenoproteins levels dropped as the severity of the condition worsened. Selenoproteins integrate the 21st amino acid, selenocysteine, into their polypeptide chain. The principal mechanism by which selenium aids biological activities is through this mechanism. In humans, there are at...

Dendritic cells as potential initiators of immune-mediated hypertensive disorders

Current knowledge suggests the involvement of both innate and adaptive immunity in the pathophysiology of hypertension and hypertension-mediated organ damage (HMOD) [1]. Antigen-presenting cells (APCs), such as dendritic cells (DCs), play a pivotal role in the initiation of adaptive immunity, which may contribute to vascular and kidney injury in hypertension through T cell activation [2]. DCs are mainly derived from hematopoietic bone marrow progenitor cells and exist in an immature state in blood. After exposure to pathogens, DCs are activated to the mature form and migrate to lymph nodes with the capability to induce an adaptive immune response. Peripheral DCs are divided into two subsets, namely, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). The former are characterized by CD11c expression and have a high capacity to produce proinflammatory cytokines (e.g., interleukin (IL)-6, IL-12 and IL-23), while the latter express CD123 and preferentially secrete type I interferon (IFN) to protect against viral infection. Both subsets of DCs play roles not only in infectious diseases but also in the development of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. However, the distribution of DC subsets may vary from disease to disease. An mDC/pDC imbalance was reported in coronary heart disease patients by Shi et al. in 2007 [3], but its significance has not been rigorously evaluated in the context of hypertension.