scholarly journals Apoptotic cells for therapeutic use in cytokine storm associated with sepsis

2020 ◽  
Author(s):  
Peter Vernon van Heerden ◽  
Avraham Abutbul ◽  
Sigal Sviri ◽  
Eitan Zlotnik ◽  
Ahmad Nama ◽  
...  
Keyword(s):  
Organ Dysfunction ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Cytokine Storm ◽  
Serious Adverse Events ◽  
Immune Modulators ◽  
Link Type ◽  
Lengths Of Stay ◽  
Hospital Stays ◽  
Historical Controls

SummaryBackgroundSepsis has no proven specific pharmacologic treatment. Reported mortality in sepsis ranges from 30%–45%. This study was designed to determine the safety preliminary efficacy of allogenic apoptotic cells administered for immunomodulation in septic patients.MethodsThe primary aim of this phase IB study was to determine the safety profile of apoptotic cell infusion in subjects presenting to the emergency room with sepsis. Sepsis was determined by clinical infections and Sequential Organ Failure Assessment (SOFA) scores >2. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality, that were compared to historical controls. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action using Luminex® analysis.FindingsTen patients were treated with apoptotic cells, administered as a single dose or two sequential doses. All 10 patients had mild-to-moderate sepsis with a SOFA score range of 2–6 upon entering the study. No serious adverse events (SAEs) and no related AEs were reported. All 10 study subjects survived while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU lengths of stay compared to matched historical controls (p<0·0001). All patients had both elevated pro- and anti-inflammatory cytokines, chemokines and additional immune modulators that gradually decreased following treatment.InterpretationAdministration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm.Trial registrationClinicalTrials.gov Identifier: NCT03925857FundingThe study was sponsored by Enlivex Therapeutics Ltd.

scholarly journals Apoptotic Cells for Therapeutic Use in Cytokine Storm Associated With Sepsis– A Phase Ib Clinical Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
Peter Vernon van Heerden ◽  
Avraham Abutbul ◽  
Sigal Sviri ◽  
Eitan Zlotnick ◽  
Ahmad Nama ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Emergency Room ◽  
Organ Dysfunction ◽  
Apoptotic Cells ◽  
Cytokine Storm ◽  
Phase Ib ◽  
Immune Modulator ◽  
Hospital Stays ◽  
Historical Controls

BackgroundSepsis has no proven specific pharmacologic treatment and reported mortality ranges from 30%–45%. The primary aim of this phase IB study was to determine the safety profile of Allocetra™-OTS (early apoptotic cell) infusion in subjects presenting to the emergency room with sepsis. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action.MethodsTen patients presenting to the emergency room at the Hadassah Medical Center with sepsis were enrolled in this phase Ib clinical study. Enrolled patients were males and females aged 51–83 years, who had a Sequential Organ Failure Assessment (SOFA) score ≥2 above baseline and were septic due to presumed infection. Allocetra™-OTS was administered as a single dose (day +1) or in two doses of 140×106 cells/kg on (day +1 and +3), following initiation of standard-of-care (SOC) treatment for septic patients. Safety was evaluated by serious adverse events (SAEs) and adverse events (AEs). Organ dysfunction, ICU and hospital stays, and mortality, were compared to historical controls. Immune modulator agents were measured using Luminex® multiplex analysis.ResultsAll 10 patients had mild-to-moderate sepsis with SOFA scores ranging from 2–6 upon entering the study. No SAEs and no related AEs were reported. All 10 study subjects survived, while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU stays compared to matched historical controls (p&lt;0.0001). All patients had both elevated pro- and anti-inflammatory cytokines, chemokines, and additional immune modulators that gradually decreased following treatment.ConclusionAdministration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm.Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT03925857. (https://clinicaltrials.gov/ct2/show/study/NCT03925857).

scholarly journals The inflammatory response induced by Pseudomonas aeruginosa in macrophages enhances apoptotic cell removal

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adriana Valeria Jäger ◽  
Paula Arias ◽  
Maria Virginia Tribulatti ◽  
Marcela Adriana Brocco ◽  
Maria Victoria Pepe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Apoptotic Cell ◽  
Bacterial Pathogen ◽  
Environmental Cues ◽  
Apoptotic Cells ◽  
Phagocytic Function ◽  
Inflammatory Stimulus ◽  
Inflammatory Conditions

AbstractPathogens phagocytosis and the uptake of apoptotic cells (efferocytosis) are essential macrophages tasks, classically considered as mutually exclusive. Macrophages have been observed to polarize into either pro-inflammatory/microbicidal or anti-inflammatory/efferocytic phenotypes. However, macrophage functions have shown to be more complex. Furthermore, little is known about the regulation of efferocytosis under inflammatory conditions. In this study, we elucidate the modulation of the macrophage efferocytic function during an inflammatory stimulus. We find that bone marrow-derived macrophages (BMDM) are very efficient in engulfing both the bacterial pathogen Pseudomonas aeruginosa and apoptotic cells. BMDM showed a high bactericidal capacity unaffected by the concomitant presence of apoptotic material. Plasticity in macrophage programming, in response to changing environmental cues, may modulate efferocytic capability. In this work, we further show that, after phagocyting and processing Pseudomonas aeruginosa, macrophages highly increase their efferocytic capacity without affecting their phagocytic function. Moreover, we demonstrate that Pseudomonas aeruginosa enhances efferocytosis of these phagocytes through the IL-6 signaling pathway. Our results show that the inflammatory response generated by the bacterial processing enhances these macrophages’ capacity to control inflammation through an increased efferocytosis.

scholarly journals Cytotoxicity, Antiproliferative Effects, and Apoptosis Induction of Methanolic Extract ofCynometra caulifloraLinn. Whole Fruit on Human Promyelocytic Leukemia HL-60 Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
T-Johari S. A. Tajudin ◽  
Nashriyah Mat ◽  
Abu Bakar Siti-Aishah ◽  
A. Aziz M. Yusran ◽  
Afnani Alwi ◽  
...  
Keyword(s):  
Cell Death ◽  
Methanolic Extract ◽  
Apoptotic Cell ◽  
Mouse Fibroblast ◽  
Promyelocytic Leukemia ◽  
Apoptotic Cell Death ◽  
Apoptotic Cells ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Methanolic extract ofCynometra cauliflorawhole fruit was assayed for cytotoxicity against the human promyelocytic leukemia HL-60 and the normal mouse fibroblast NIH/3T3 cell lines by using the MTT assay. The CD50of the extract for 72 hours was 0.9 μg/mL whereas the value for the cytotoxic drug vincristine was 0.2 μg/mL. The viability of the NIH/3T3 cells was at 80.0% when treated at 15.0 μg/mL. The extract inhibited HL-60 cell proliferation with dose dependence. AO/PI staining of HL-60 cells treated with the extract revealed that majority of cells were in the apoptotic cell death mode. Flow cytometry analysis of HL-60 cells treated at CD50of the extract showed that the early apoptotic cells were 31.0, 26.3 and 19.9% at 24, 48, and 72 hours treatment, respectively. The percentage of late apoptotic cells was increased from 62.0 at 24 hours to 64.1 and 70.2 at 48 and 72 hours, respectively. Meanwhile, percent of necrotic cells were 4.9, 6.6, and 8.5 at 24, 48, and 72 hours, respectively. This study has shown that the methanolic extract ofC. cauliflorawhole fruit was cytotoxic towards HL-60 cells and induced the cells into apoptotic cell death mode, but less cytotoxic towards NIH/3T3 cells.

Repurposing Domperidone in Secondary Progressive MS

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011863
Author(s):  
Marcus W. Koch ◽  
Kayla Sage ◽  
Sharanjit Kaur ◽  
Janet Kim ◽  
Graziela Cerchiaro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Phase 2 ◽  
Disability Progression ◽  
Two Stage ◽  
Serious Adverse Events ◽  
Secondary Progressive ◽  
Link Type

ObjectiveTo assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon two-stage design.MethodsWe enrolled patients in an open-label, Simon two-stage, single-center, phase 2, single-arm futility trial at the Calgary MS Clinic if they met the following criteria: age 18–60 years, SPMS, screening EDSS score of 4.0–6.5 and screening T25FW of 9 seconds or more. Patients received domperidone 10 mg QID for one year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by 20% or more at 12 months compared to at baseline. This trial is registered with ClinicalTrials.gov, number NCT02308137.ResultsBetween February 13, 2015 and January 3, 2020, 110 patients were screened, 81 received treatment, 64 completed follow-up, of whom 62 were analysed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40%, and above the pre-defined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.ConclusionsDomperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon two-stage trial model may be a useful model for phase 2 studies in progressive MS.Classification of evidenceThis study provides Class III evidence that in individuals with secondary progressive multiple sclerosis participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.

scholarly journals Hydrocortisone decreases apoptosis in jejunum of horses subjected to experimental ischemia and reperfusion

2011 ◽  
Vol 31 (6) ◽  
pp. 471-476 ◽  
Author(s):  
Geraldo Eleno S. Alves ◽  
Heloisa M.F. Mendes ◽  
Tiago G.S. Alves ◽  
Rafael R. Faleiros ◽  
Anilton C. Vasconcelos ◽  
...  
Keyword(s):  
Cell Death ◽  
Time Course ◽  
Apoptotic Cell ◽  
Treated Group ◽  
Apoptotic Cell Death ◽  
Apoptotic Cells ◽  
Ischemia And Reperfusion ◽  
Beneficial Effects ◽  
Time Zero ◽  
Venous Ischemia

In order to evaluate the effect of hydrocortisone on apoptosis in the jejunum of horses subjected to ischemia and reperfusion, ten horses were paired and grouped into two groups - treated (n=5) and non treated (n=5). Segments of the jejunum were used as controls (C), or as venous ischemia (VIsc), which were subjected to 2h of ischemia followed by 2 or 12h of reperfusion. C samples were collected at time zero (prior to ischemia) and VIsc samples were collected at 2h of ischemia and at 2 and 12h of reperfusion. TUNEL positive apoptotic cells were counted in 10 microscopical fields in deep mucosa from each horse throughout the time course. After 12h of reperfusion, the number of apoptotic cells in treated group were significantly lower than in untreated animals, indicating that hydrocortisone inhibits apoptosis. These results indicate that hydrocortisone has a beneficial effects favoring the maintenance of jejunal integrity in horses with ischemia and reperfusion injuries by preventing apoptotic cell death.

scholarly journals Different Roles of a Rat Cortical Thymic Epithelial Cell LineIn Vitroon Thymocytes and Thymocyte Hybridoma Cells: Phagocytosis, Induction of Apoptosis, Nursing and Growth Promoting Activities

2002 ◽  
Vol 9 (2) ◽  
pp. 63-72 ◽  
Author(s):  
Dragana Vucevic ◽  
Miodrag Colic ◽  
Petar Popovic ◽  
Sonja Gašic
Keyword(s):  
Epithelial Cell ◽  
Cell Line ◽  
Apoptotic Cell ◽  
Hybridoma Cells ◽  
Thymic Epithelial Cell ◽  
Apoptotic Cells ◽  
Th Cells ◽  
Nursing Activity ◽  
Induction Of Apoptosis ◽  
Stimulation Of

In this work, the interaction between a rat cortical thymic epithelial cell (TEC) line (R-TNC.1) with nursing activity and thymocytes as well as BWRT 8 thymocyte hybridoma (TH) cells has been studied. The R-TNC.1 cell line significantly bound thymocytes and TH. Binding was stronger during the first 30 min of cell incubation and was followed by a progressive deadhesion. Among adherent thymocytes the proportion of apoptotic cells increased with culture time which was a consequence of higher capacity of the line for binding of apoptotic than viable cells and induction of apoptosis in a subset of adherent thymocytes. Emperiopolesis activity of this thymic nurse cell (TNC) line was manifested by engulfment of thymocytes as well as TH cells. A subset of viable intra-TNC thymocytes has been triggered to die by apoptosis, whereas other internalized thymocytes have been stimulated to proliferate, as measured by an increase in the percentage of cells in mitosis and higher incorporation of bromodeoxyuridine (BrdU), in comparison to thymocytes cultivated alone. A significant stimulation of proliferation of engulfed TH cells was also observed. The R-TNC.1 cell line efficiently phagocytosed both apoptotic thymocytes and TH, and the process is followed by intra-TNC destruction of ingested cells. Cumulatively, these results suggest different role of the R-TNC.1 clone: phagocytosis of apoptotic cells; induction of apoptotic cell death in a subset of both bound and internalized thymocytes and stimulation of proliferation of a subset of intra-TNC thymocytes or TH cells.

Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1734-1741 ◽  
Author(s):  
Nicolas Bertho ◽  
Henri Adamski ◽  
Louis Toujas ◽  
Martine Debove ◽  
Jean Davoust ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Immune Responses ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Tnf Α

Abstract Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a TH2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-α-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate TH1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine. (Blood. 2005;106:1734-1741)

scholarly journals Oral Janus Kinase Inhibitor for the Treatment of Rheumatoid Arthritis: Tofacitinib

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Han Ni ◽  
Soe Moe ◽  
Kay Thi Myint ◽  
Aung Htet
Keyword(s):  
Rheumatoid Arthritis ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Janus Kinase ◽  
Serious Adverse Events ◽  
Janus Kinase Inhibitor ◽  
Immune Modulators ◽  
Serious Infections

Since the introduction of immune modulators in the treatment of rheumatoid arthritis (RA), there has been hope that orally effective biologic agents would be developed. Tofacitinib, a Janus kinase inhibitor, has become the first oral biologic to receive approval for use in active RA patients. This paper reviews the efficacy and safety profile of Tofacitinib at dosages of 5 mg and 10 mg twice daily. Remarkable improvement in terms of ACR 20 response and HAQ-DI score was noted at month 3 and month 6. DAS 28-4 ESR < 2.6 achievement was noticeably obvious at month 6 for both dosages. No significant serious adverse events, serious infections, neutropenia, or anaemia were observed compared to placebo. In fact, Tofacitinib 5 mg was even found to have significant protective effect of anaemia in the meta-analysis (P=0.004). Tofacitinib has a noticeable efficacy in controlling disease activity in RA with a manageable safety profile. However, longer studies are needed for its long-term safety profile.

scholarly journals Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Toshihiko Maruyama ◽  
Yoshihiro Urade ◽  
Shigekazu Nagata
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Adenosine Monophosphate ◽  
Receptor Activation ◽  
Death Process ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
A2a Adenosine Receptor ◽  
Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

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