scholarly journals Possible Divergent Local and Peripheral Immunological Effects of Low-Dose Mesencure, an Enhanced Mesenchymal Cell Therapy, May Contribute to Its Success in Treating Severe Covid-19 Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2172-2172
Author(s):  
Tomer Bronshtein ◽  
Dror Ben David ◽  
Atara Novak ◽  
Vered Kivity ◽  
Shai Meretzki ◽  
...  
Keyword(s):  
T Cells ◽  
Low Dose ◽  
De Novo ◽  
Lung Edema ◽  
High Dose ◽  
Local Inflammation ◽  
Blood Leukocytes ◽  
Gene Encoding ◽  
Leukocyte Counts ◽  
Anti Inflammatory

Abstract Mesenchymal stromal cells (MSC) are widely investigated for treating ARDS in Covid-19. Nonetheless, these efforts are overshadowed by studies predating the pandemic that mostly failed to show MSC efficacy in ARDS and recent disappointments with repurposed MSC products. Relying on years of MSC-related experience, Bonus BioGroup developed MesenCure: An enhanced allogeneic MSC therapy for Covid-19, professionalized by a unique combination of culture conditions and optimized in ARDS-relevant models. MesenCure is currently evaluated in a Phase II study in severe Covid-19 patients and administered (IV) in three doses (1.5M cells/kg, d1, d3, d5). A Phase I/II study on ten severe patients demonstrated a significant improvement in ARDS-related parameters following MesenCure treatment. Patients were discharged within one day (median) following treatment, requiring no respiratory support. Speedy recovery from local inflammation was observed in these patients, demonstrated by a rapid reduction in diffuse lung pneumonia, from 55% of the lung area to 15% within 5-6 days from the first dose (p<0.01, Fig. A-C). A corresponding drop in CRP was detected (p<0.01), which returned to normal. A multivariate regression analysis revealed that the reduction in CRP was mainly associated with the number of doses administered and not and the time elapsed since the first dose. MesenCure efficacy may be attributable to the cells' de novo expression of the gene encoding for the IL-6 receptor, making them more responsive to inflammation than non-professionalized naïve MSC (NA-MSC); as well as >8-fold upregulation of the EDIL3 gene, encoding for an endogenous inhibitor of immune infiltration. A corresponding immunosuppressive effect of MesenCure MSCs was demonstrated in vitro, showing their ability to suppress T cells activation twice more effectively than NA-MSC. In this study, MesenCure inhibited the proliferation of primary CD4 T cells in a concentration-depended manner following non-specific activation. Over 98% inhibition was achieved in co-culture of 1:10 MSC-to-PBMC with an IC 50 of 6k MSC/200k PBMCs (r 2=1.00) compared to 12k NA-MSC/200k PBMCs (r 2=0.95). Comparable results were also obtained for CD8 T cells. Similarly, MesenCure inhibited ROS production by primary neutrophils remarkably fast and by up to 80% within less than 40 minutes following their activation (IC 50 = 19k MSC/200k neutrophils, r 2=1.00). In addition to local immunosuppressive outcomes, a significant increase in blood leukocytes was observed in patients treated with MesenCure (p<0.05, Fig. D-F). Further analysis suggested that the increase in total WBCs and neutrophils was associated with the number of MesenCure doses administered (p<0.05, Fig. G-H). In contrast, the increase in lymphocytes was time-dependent (R=0.72, Fig. I). The seemingly exclusively localized anti-inflammatory effects seen in severe patients treated with MesenCure were also observed in animal (murine) studies. An in vivo study in an acute lung injury model demonstrated a dose-dependent localized reduction in leukocyte counts in the lung fluids of animals treated with MesenCure (IV) using two dose levels. Relative to untreated animals, MesenCure reduced lung leukocyte counts by 35%-43% in animals treated with the low dose and by 62%-67% following high-dose MesenCure treatment (p<0.05). The leukocytes' clearance from the lungs was accompanied by a 41%-57% reduction in lung edema (p<0.05) following MesenCure treatment. Notably, NA-MSC did not achieve the same effect. Similar to our clinical findings, a significant increase was measured in neutrophil counts in animals treated with low-dose MesenCure (p<0.05), which decreased dramatically (p< 0.01) in animals treated with a four-times higher dose. MesenCure is administered at a much lower dose compared to other MSC products administered at up to 10M cells/kg. Considering the increase in blood leukocytes measured in patients treated with low-dose MesenCure and comparable preclinical findings, our data suggest that low-dose MesenCure could elicit a potent local anti-inflammatory effect without suppressing, and even enhancing, peripheral immunity that is needed to fight the virus. Further research is inevitably required into the mechanism behind this phenomenon. However, our results indicate MesenCure's potential in relieving local inflammation while giving the patient a fighting chance against viremia. Figure 1 Figure 1. Disclosures Bronshtein: Bonus BioGroup: Current Employment. Ben David: Bonus BioGroup: Current Employment. Novak: Bonus BioGroup: Current Employment. Kivity: Bonus BioGroup: Current Employment. Meretzki: Bonus BioGroup: Current Employment. Rozen: Bonus BioGroup: Consultancy.

scholarly journals Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Leslie A. Khawli ◽  
Vyshnavi Pachipulusu ◽  
Sharon W. Lin ◽  
Long Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Real Time ◽  
Pet Imaging ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Car T Cells ◽  
Nsg Mice ◽  
Car T

AbstractQuantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.

scholarly journals CD8+ T Cells Mediate Recovery andImmunopathology in West Nile VirusEncephalitis

2003 ◽  
Vol 77 (24) ◽  
pp. 13323-13334 ◽  
Author(s):  
Yang Wang ◽  
Mario Lobigs ◽  
Eva Lee ◽  
Arno Müllbacher
Keyword(s):  
T Cells ◽  
Dose Group ◽  
Low Dose ◽  
Neuronal Degeneration ◽  
High Dose ◽  
West Nile ◽  
Activation Markers ◽  
High Doses ◽  
The Brain ◽  
Deficient Mice

ABSTRACT C57BL/6J mice infected intravenously with the Sarafend strain of West Nile virus (WNV) develop a characteristic central nervous system (CNS) disease, including an acute inflammatory reaction. Dose response studies indicate two distinct kinetics of mortality. At high doses of infection (108 PFU), direct infection of the brain occurred within 24 h, resulting in 100% mortality with a 6-day mean survival time (MST), and there was minimal destruction of neural tissue. A low dose (103 PFU) of infection resulted in 27% mortality (MST, 11 days), and virus could be detected in the CNS 7 days postinfection (p.i.). Virus was present in the hypogastric lymph nodes and spleens at days 4 to 7 p.i. Histology of the brains revealed neuronal degeneration and inflammation within leptomeninges and brain parenchyma. Inflammatory cell infiltration was detectable in brains from day 4 p.i. onward in the high-dose group and from day 7 p.i. in the low-dose group, with the severity of infiltration increasing over time. The cellular infiltrates in brain consisted predominantly of CD8+, but not CD4+, T cells. CD8+ T cells in the brain and the spleen expressed the activation markers CD69 early and expressed CD25 at later time points. CD8+ T-cell-deficient mice infected with 103 PFU of WNV showed increased mortalities but prolonged MST and early infection of the CNS compared to wild-type mice. Using high doses of virus in CD8-deficient mice leads to increased survival. These results provide evidence that CD8+ T cells are involved in both recovery and immunopathology in WNV infection.

scholarly journals Dose-dependent roles of aspirin and other non-steroidal anti-inflammatory drugs in abnormal bone remodeling and skeletal regeneration

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yong Xie ◽  
Meng Pan ◽  
Yanpan Gao ◽  
Licheng Zhang ◽  
Wei Ge ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Remodeling ◽  
Low Dose ◽  
High Dose ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Dose Dependent ◽  
High Dose Aspirin

AbstractThe failure of remodeling process that constantly regenerates effete, aged bone is highly associated with bone nonunion and degenerative bone diseases. Numerous studies have demonstrated that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) activate cytokines and mediators on osteoclasts, osteoblasts and their constituent progenitor cells located around the remodeling area. These cells contribute to a complex metabolic scenario, resulting in degradative or synthetic functions for bone mineral tissues. The spatiotemporal effects of aspirin and NSAIDs in the bone remodeling are controversial according the specific therapeutic doses used for different clinical conditions. Herein, we review in vitro, in vivo, and clinical studies on the dose-dependent roles of aspirin and NSAIDs in bone remodeling. Our results show that low-dose aspirin (< 100 μg/mL), which is widely recommended for prevention of thrombosis, is very likely to be benefit for maintaining bone mass and qualities by activation of osteoblastic bone formation and inhibition of osteoclast activities via cyclooxygenase-independent manner. While, the roles of high-dose aspirin (150–300 μg/mL) and other NSAIDs in bone self-regeneration and fracture-healing process are difficult to elucidate owing to their dual effects on osteoclast activity and bone formation of osteoblast. In conclusion, this study highlighted the potential clinical applications of low-dose aspirin in abnormal bone remodeling as well as the risks of high-dose aspirin and other NSAIDs for relieving pain and anti-inflammation in fractures and orthopedic operations.

Comparative study of high-dose Xuezhikang and low-dose Xuezhikang plus ezetimibe on pro- and anti-inflammatory markers

2013 ◽  
Vol 8 (1) ◽  
pp. 151-157 ◽  
Author(s):  
Jun Liu ◽  
Song-Hui Luo ◽  
Ping Qing ◽  
Long-Hui Di ◽  
Xiang-Dong You ◽  
...  
Keyword(s):  
Comparative Study ◽  
Inflammatory Markers ◽  
Low Dose ◽  
High Dose ◽  
Anti Inflammatory

scholarly journals CD8+-T-Cell Response to Secreted and Nonsecreted Antigens Delivered by Recombinant Listeria monocytogenes during Secondary Infection

2002 ◽  
Vol 70 (1) ◽  
pp. 153-162 ◽  
Author(s):  
Amy R. Tvinnereim ◽  
Sara E. Hamilton ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Cell Response ◽  
Low Dose ◽  
Recombinant Antigen ◽  
T Cell Response ◽  
Vector System ◽  
High Dose ◽  
The Impact

ABSTRACT Understanding how existing antivector immunity impacts live vaccine delivery systems is critical when the same vector system may be used to deliver different antigens. We addressed the impact of antivector immunity, elicited by immunization with attenuated actA-deficient Listeria monocytogenes, on the CD8+-T-cell response to a well-characterized lymphocytic choriomeningitis virus epitope, NP118-126, delivered by infection with recombinant L. monocytogenes. Challenges of immune mice with actA-deficient and with wild-type recombinant L. monocytogenes generated similar numbers of CD8+ T cells specific for the NP118-126 epitope. High-dose immunization with actA-deficient L. monocytogenes resulted in substantial numbers of CD8+ T cells specific for the L. monocytogenes LLO91-99 epitope in the effector and memory stages of the T-cell response. Challenge of these immune mice with recombinant L. monocytogenes resulted in rapid control of the infection and decreased CD8+-T-cell responses against both the secreted and nonsecreted form of the recombinant antigen compared to the response of naïve mice. In contrast, mice immunized with a low dose of actA-deficient L. monocytogenes had ∼10-fold fewer effector and memory T cells specific for LLO91-99 and a substantially higher CD8+-T-cell response against the recombinant antigen after challenge with recombinant L. monocytogenes. Although mice immunized with low-dose actA-deficient L. monocytogenes had a substantial recall response to LLO91-99, which reached the same levels by 5 to 7 days postchallenge as that in high-dose-immunized mice, they exhibited decreased ability to control L. monocytogenes replication. Thus, the level of antivector immunity impacts the control of infection and efficiency of priming responses against new antigens introduced with the same vector.

The Absence of Vasoactive Intestinal Peptide Augments Allo-Reactivity and the Anti-Viral Response in Bone Marrow Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3267-3267
Author(s):  
Lauren T. Southerland ◽  
Jian-Ming Li ◽  
Sohrab Hossain ◽  
Cynthia Giver ◽  
Wayne Harris ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Low Dose ◽  
T Cell Response ◽  
High Dose ◽  
Mcmv Infection

Abstract Background: The severe morbidity and mortality associated with bone marrow transplantation (BMT) is caused by uninhibited immune responses to alloantigen and suppressed immune responses to pathogens. Vasoactive Intestinal Peptide (VIP) is an immunomodulatory neuropeptide produced by T-cells and nerve fibers in peripheral lymphoid organs that suppresses immune responses by induction of tolerogenic dendritic cells. In order to determine the immunoregulatory effects of VIP, we examined T-cell immune responses to allo- and viral-antigens in VIP knockout (KO) mice and mouse BMT recipients of hematopoietic cells from VIP KO donors. Methods: VIP KO mice and VIP WT littermates were infected with lethal or sub-lethal doses (5 × 104− 5 × 105 PFU) of murine cytomegalovirus (mCMV) and the T-cell response to viral antigen was measured by flow cytometry for mCMV peptide-MHC class 1-tetramer+ CD8+ T-cells. We transplanted 5 × 106 BM plus 1 × 106 splenocytes (SP) either from VIP KO or VIP WT donors in an C57BL/6 to F1(BL/6 × Balb/c) allo-BMT model and assessed survival, GvHD, donor T-cell expansion, chimerism, and response to mCMV vaccination and mCMV infection. Results: B-cell, αβ and γδ T-cell, CD8+ T-cell, CD11b+ myeloid cell, and dendritic cell numbers were equivalent between VIP KO and WT mice, while VIP KO mice had higher number of CD4+ and CD4+CD62L+CD25+ T-cells. Non-transplanted VIP KO mice survived mCMV infection better compared to VIP WT, with a brisker anti-viral T-cell response in the blood. In the allogeneic BMT setting, recipients of VIP KO BM plus VIP KO SP had more weight loss and lower (40%) 100 day post-transplant survival compared to the recipients of VIP KO BM plus WT SP (80% survival), recipients of WT BM plus KO SP (100% survival), and recipients of WT BM plus WT SP (80% survival). Recipients of VIP KO grafts had a significantly greater anti-mCMV response that peaked four days earlier than the tetramer response of mice transplanted with WT cells. This increased anti-viral response to vaccination correlated with a greater and more rapid T-cell response to secondary viral challenge. Conclusions: These experiments suggest that the absence of all VIP in the body, or the absence of VIP in a transplanted immune system, enhances anti-viral immunity and allo-immune responses. Modulation of the VIP pathway is a novel method to regulate post-transplant immunity. Figure 1: VIP knockout(KO) mice have an increased CMV tetramer response. VIP KO and VIP WT mice were infected (day 0) with either a sub-lethal low dose (5 × 10^4 PFU) or a lethal high dose (5 × 10^5 PFU) of CMV. Peripheral blood was stained for T cell markers and tetramer and analyzed by flow cytometry. On day 3, high dosed VIP KO mice had a higher number of tetramer positive CD8 T cells and better survival than WT mice (all high dose VIP WT died prior to day 10). VIP KO mice had a significant increase in tetramer positive CD8 T cells between days 3 and 10. *** p<0.01, difference between VIP KO and VIP WT littermate at designated dose level and day. Figure 1:. VIP knockout(KO) mice have an increased CMV tetramer response. VIP KO and VIP WT mice were infected (day 0) with either a sub-lethal low dose (5 × 10^4 PFU) or a lethal high dose (5 × 10^5 PFU) of CMV. Peripheral blood was stained for T cell markers and tetramer and analyzed by flow cytometry. On day 3, high dosed VIP KO mice had a higher number of tetramer positive CD8 T cells and better survival than WT mice (all high dose VIP WT died prior to day 10). VIP KO mice had a significant increase in tetramer positive CD8 T cells between days 3 and 10. *** p<0.01, difference between VIP KO and VIP WT littermate at designated dose level and day.

De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1240-1247 ◽  
Author(s):  
Thierry Dervieux ◽  
Timothy L. Brenner ◽  
Yuen Y. Hon ◽  
Yinmei Zhou ◽  
Michael L. Hancock ◽  
...  
Keyword(s):  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Initial Therapy ◽  
High Dose ◽  
Purine Synthesis ◽  
Percentage Decrease ◽  
Before And After ◽  
Leukocyte Counts ◽  
B Lineage

Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m2) or high-dose MTX (HDMTX: intravenous 1 g/m2) followed by intravenous MP; or intravenous MP alone (1 g/m2), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 ± 189 vs 250 ± 38 fmol/nmol/h;P = .001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P &lt; .001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (−50% ± 4%, −56% ± 3%, and − 20% ± 4%, respectively;P &lt; .0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (−63% ± 4% vs −37% ± 4%; P &lt; .0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 ± 298 vs 1075 ± 114 pmol/109 cells;P &lt; .01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P &lt; .001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after HDMTX.

scholarly journals RelB Sustains IκBα Expression during Endotoxin Tolerance

2008 ◽  
Vol 16 (1) ◽  
pp. 104-110 ◽  
Author(s):  
Xiaoping Chen ◽  
Barbara K. Yoza ◽  
Mohamed El Gazzar ◽  
Jean Y. Q. Hu ◽  
Sue L. Cousart ◽  
...  
Keyword(s):  
De Novo ◽  
Cell Model ◽  
Endotoxin Tolerance ◽  
Proximal Promoter ◽  
Blood Leukocytes ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Immunity Genes ◽  
Chromatin Structural ◽  
Anti Inflammatory

ABSTRACT Transcription factors and chromatin structural modifiers induce clinically relevant epigenetic modifications of blood leukocytes during severe systemic inflammation (SSI) in humans and animals. These changes affect genes with distinct functions, as exemplified by the silencing of a set of acute proinflammatory genes and the sustained expression of a group of antimicrobial and anti-inflammatory genes. This paradigm is closely mimicked in the THP-1 human promonocyte cell model of lipopolysaccharide (LPS) endotoxin tolerance. We previously reported that LPS-induced de novo expression of RelB is required for generating tolerance to interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) expression. RelB represses transcription by binding with heterochromatic protein 1 α (HP1α) to the proximal promoters of IL-1β and TNF-α. In contrast, we report herein that RelB is required for sustained expression of anti-inflammatory IκBα in LPS-tolerant THP-1 cells. RelB transcription activation requires binding to the IκBα proximal promoter along with NF-κB p50 and is associated with an apparent dimer exchange with p65. We also observed that RelB induced during human SSI binds to the IκBα proximal promoter of circulating leukocytes. We conclude that RelB functions as a dual transcription regulator during LPS tolerance and human SSI by activating and repressing innate immunity genes.

scholarly journals Anti-rheumatic drugs as potential anti-inflammatory, immunomodulatory agents against COVID-19: A systematic review

2021 ◽  
Author(s):  
Reza Sinaei ◽  
Sara Pezeshki ◽  
Ali Asadipour ◽  
Reza Shiari ◽  
Roya Sinaei ◽  
...  
Keyword(s):  
Systematic Review ◽  
Low Dose ◽  
Kinase Inhibitors ◽  
Adverse Outcomes ◽  
Janus Kinase ◽  
Cochrane Library ◽  
High Dose ◽  
Cytokine Storm ◽  
Early Stages ◽  
Anti Inflammatory

Background: The effective responses of both innate and adaptive immunity are crucial in combating Novel-Coronavirus-2 infection. An excessive response may lead to cytokine storm, which is a challenging problem in therapeutic strategies. Methods: A systematic review was carried out by searching OVID MEDLINE, PUBMED, Google Scholar, and Cochrane library databases from inception until August 2, 2020, for anti-inflammatory and immunomodulatory drugs against coronavirus disease 2019 (COVID-19). Results: The results of the effectiveness of Hydroxychloroquine are just like a sinusoidal diagram and in a state of ambiguity. Thalidomide was effective in some cases but has not yet been proven. Low-dose Corticosteroids may be effective in the early stages of the illness as a bridge. There is no evidence of benefits or adverse outcomes for the use of non-steroidal anti-inflammatory drugs and Cyclosporine-A. In some critically ill patients, Interleukin-6 (IL-6) and IL-1 blockers and to some extent Tumor-Necrosis-Factor-α and Janus-Kinase inhibitors are useful. Finally, high-dose intravenous immunoglobulin reversed the deterioration of patients in most trials. Conclusion: One strategy behind the treatments for COVID-19 is based on breaking the cytokine storm. Although avoiding the suppression of anti-viral immunity is crucial by choosing the weaker and more selective anti-inflammatories, some strategies are kept for hyper-inflammatory situations. Scheduling of treatment is also important. Although low-dose steroids may be effective in the early stages of the illness, "Tocilizumab" is more effective in severe situations, when the IL-6 level is high and other drugs are ineffective. Therefore, consideration should be given to each patient separately.

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