key: cord-1005640-y2wpoeo3 authors: Esmaeilzadeh, Abdolreza; Elahi, Reza title: Immunobiology and immunotherapy of COVID‐19: A clinically updated overview date: 2020-10-06 journal: J Cell Physiol DOI: 10.1002/jcp.30076 sha: 36450e0e247672a953a943008ba25b17d7450084 doc_id: 1005640 cord_uid: y2wpoeo3 Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a new member of the coronavirus family that can cause coronavirus disease 2019 (COVID‐19). COVID‐9 has become a global pandemic with severe health issues around the world. Identifying the accurate immunopathogenesis of the COVID‐19 and the immune response against SARS‐CoV‐2 is necessary for the development of therapeutic approaches and rational drug design. This paper aims to overview the updated clinical data on the immunopathogenesis of the COVID‐19 and review the innate and adaptive immune response to SARS‐CoV‐2. Also, challenges of the immune response to SARS‐CoV‐2 leading to dysfunctional immune response and their contribution to the progression of the disease have been discussed. To achieve a more efficient immune response, multiple methods could be applied, including regulation of the immune response, augmentation of the immune system against the virus, inhibition of the dysfunctional immune checkpoints, and inhibition of the viral replication/infection. Based on the immune response against SARS‐CoV‐2 and its dysfunction, we introduce potential immunotherapies as well as reviewing recruiting/completed clinical trials of COVID‐19. SARS-CoV-2 is mainly transmitted through close contact by respiratory droplets of the infected patients. Also, positive fecal specimens of the infected patients have increased the possibility of fecal-oral transmission. Bare contact with infected surfaces has also been suggested as a potential route of infection of COVID-19 (Meselson, 2020) . The incubation period of the COVID-19 is estimated 1-14 days after exposure. A study has reported the incubation period up to 27 days after exposure; however, most patients exhibit symptoms approximately after 5 days (Lauer et al., 2020) . There is a wide range of variability in clinical symptoms of the patients with COVID-19, with most of the patients remaining asymptomatic. In symptomatic patients, initial clinical symptoms include fever, myalgia, pharyngalgia, sore throat, dry cough, dyspnea (shortness of breath), fatigue, and malaise. Diarrhea and loss of appetite can also be among the early signs of the disease. Despite SARS and MERS that do not accompany gastrointestinal symptoms, COVID-19 can cause gastrointestinal tract symptoms such as diarrhea (Holshue et al., 2020; Zhang, Wang et al., 2020) . Also, headache and hemoptysis have been reported in some patients . Most of the patients show mild symptoms of infection with SARS-CoV-2; however, in a small proportion of the patients, the respiratory symptoms can worsen and lead to a severe respiratory syndrome that needs intensive care. According to documents, most of the mortalities were reported to happen in elderly patients or patients with multiple comorbidities, including cardiovascular diseases, respiratory diseases, diabetes mellitus, hypertension, and immune-compromised patients, such as cancer. Also, the mortality rate varies based on age with most of the deaths occurring in older male patients (Jung et al., 2020) . COVID-19 has some nonspecific laboratory signs. The laboratory signs of the COVID-19 include leukocytosis, lymphopenia, increased C-reactive protein, increased D-dimer, and increased lactate dehydrogenase. Procalcitonin is not reported being increased except in patients with severe disease who needed intensive care . In the chest X-ray, patchy infiltrations with diffuse ground-glass patchy shadow can be observed. In the chest computed tomography (chest-CT), bilateral ground-glass opacification and diffuse consolidation are the most specific signs for COVID-19-related pneumonia (Bernheim et al., 2020) . Multiple tests can be used to confirm the diagnosis. The most common definitive test for COVID-19 is the viral RNA detecting technique, real-time quantitative polymerase chain reaction (RT-qPCR). Despite the high sensitivity of the RT-qPCR test for SARS-COV-2, the false-negative results have been reported in patients with typical clinical symptoms and chest-CT results (Yelin et al., 2020) . Thus, CT and clinical symptoms must be attended in the evaluation of the patients with negative RT-qPCR results. A recent study reported the sensitivity of chest-CT to be higher in comparison to RT-qPCR. Thus, in clinically highly suspicious patients with negative RT-qPCR test, chest-CT and repeating RT-qPCR has been proposed. Moreover, antiviral Immunoglobulin M (IgM)/IgG-detecting kits have been studied and produced by multiple companies. The SARS-CoV-2 is transmitted through droplets, which are distributed by coughing and sneezing from infected patients. Also, the positive-viral tested neonates born from infected pregnant women have suggested the vertical transmission of the virus to the infants; however, unlike SARS and MERS, COVID-19 does not seem to cause maternal mortality or intrauterine growth retardation in humans (L. Wang et al., 2020) . After being transmitted, the first location that the virus starts to replicate is the airway epithelial cells. As the disease progresses, the virus transmits to the lower sections of the airway. The main host cells for SARS-CoV-2 are the type II pneumocytes of the lung and the enterocytes of the gut. Similar to SARS, SARS-CoV-2 utilizes the angiotensin-converting enzyme-2 (ACE-2) receptor to enter the host cell; however, the presence of the ACE-2 receptor is not the sole factor that determines the infection of the tissue with SARS-CoV-2 (W. Li et al., 2003; . A recent study has demonstrated that SARS-COV-2 possesses 10-20 fold more affinity for the ACE-2 receptor (X. T. . Through the spike (S) glycoprotein of its receptor-binding domain (RBD), SARS-CoV-2 binds to the ACE-2 receptor. Spike glycoprotein of the SARS-CoV-2 is composed of two sections, S1 and S2. S1 is responsible for the binding of the viral RBD to the host cell receptor, and S2 is responsible for the fusion of the virus to the host cell membrane. Since the ACE-2 receptor is highly expressed by the epithelium of the small intestine, upper respiratory tract, and alveolar pneumocytes, COVID-19 can enter the cells of these two organs and cause upper respiratory and gastrointestinal symptoms (X. . After the infection with SARS-CoV, the expression of the ACE-2 receptor by lung cells has reported being decreased (Kuba et al., 2006) . The downregulation of the ACE-2 expression by lung cells is associated with acute lung injury (Imai et al., 2005) . Therefore, ACE-2 downregulation in lung cells is another pathologic mechanism of SARS-CoV leading to acute lung injury and acute respiratory distress syndrome (ARDS). Considering the application of the same receptor for cell entrance and the similarity of the pathogenesis of SARS-COV with SARS-CoV-2, the downregulation of ACE-2 could be another possible mechanism of acute lung injury in the pathogenesis of SARS-CoV-2. All other organs of the body that express the ACE-2 receptor could also be infected with SARS-COV-2. As an example, a study (Jia et al., 2020) has investigated the infection of the adipose tissue by SARS-COV-2. This study indicated that since adipose tissue expresses the ACE-2 receptor, adipose cells can be infected with SARS-COV-2. As mentioned, pulmonary pneumocytes are the most common lung cells infected by SARS-CoV-2. The cytotoxic effects of the virus on pneumocytes stimulate the release of inflammatory mediators that trigger a local immune response. Additionally, resident alveolar macrophages exert an inflammatory immune response against the virus by producing proinflammatory cytokines and chemokines, such as interferon (IFN)-γ, IP-10, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. The release of these proinflammatory cytokines and chemokines to the blood stimulates an inflammatory response in the lung by recruiting blood monocytes and T-lymphocytes. The inflammatory response can vary from mild inflammation to severe inflammation. In most cases, the immune response is capable of eliminating the virus; however, deficient immune response or the respiratory hyperinflammation can lead to severe respiratory failure in severe cases. Severe pulmonary inflammation also increases capillary leakage that can cause ARDS (Rockx et al., 2020) . Thus, the immune response against SARS-CoV-2 and the severity of the inflammation are two major factors that define the outcome in patients with COVID-19. The analysis of the lung autopsy samples of the patients with COVID-19 has exhibited the patients to have cellular fibromyxoid exudates and desquamation of the pneumocytes. Also, hyaline membrane formation and pulmonary edema were seen, which identifies the progression of the ARDS as the leading cause of death. Similar to SARS-CoV, the uncontrolled infiltration of the immune cells and unrestrained production of inflammatory cytokines are the main factors that contribute to the progression of cytokine storm and ARDS in COVID-19. ARDS reduces the oxygen-exchange capacity of the lungs and causes respiratory failure, which can lead to patient death (Z. . Multiple-organ failure is one of the consequences of the cytokine storm that can lead to dysfunction of the kidneys, liver, heart, and other end organs. In conclusion, the immune response is the factor that defines whether the infection with SARS-CoV-2 is going to be promptly cleaned, leading to mild disease, or it is going to develop severe disease and respiratory failure (F. . In addition to the immune system, the ABO blood group is another factor that could affect the susceptibility of the individuals to COVID-19. In a recent study, Zhao et al. (2020) inspected the relationship between the ABO blood and COVID-19 infection. This study demonstrated that individuals with A blood group were at an increased risk for COVID-19 (OR = 1.45), while O blood group individuals had reduced risk for COVID-19 infection (OR = 45; Ellinghaus et al., 2020) . The lower susceptibility of O blood group patients can be explained by the presence of the cross-neutralizing anti-blood group antibodies against SARS-CoV-2 in their serum. These anti-blood group antibodies, and especially anti-A antibodies, have shown neutralizing activity against the SARS-CoV-2, and can thus reduce the risk of infection with SARS-CoV-2 in patients with O blood group . One of the most common laboratory characteristics of the COVID-19 is lymphopenia (Z. Wu & McGoogan, 2020) , which is commonly accompanied by an increase in the number of neutrophils. There are several reasons for lymphopenia in COVID-19. The pulmonary infiltration of the lymphocytes, apoptosis/pyroptosis of the lymphocytes, lateral margination, and infection of the lymphocytes by SARS-CoV-2, are the most common reasons leading to lymphopenia (Tay et al., 2020) . Studies have demonstrated that the lymphopenia mostly results from the reduced number of CD8 + cells, rather than CD4 + T cells, B cells, or NK cells (Wan et al., 2020) . Since CD8 + cells have an essential role in the antiviral immune response against SARS-COV-2-infected cells, the reduction in their number weakens the antiviral immunity of the patients. Thus, lymphopenia has been reported to be more common in severe cases, occurring in 63%-70.3% of critically ill patients (Tavakolpour et al., 2020) . Accordingly, lymphopenia has been proposed as a prognostic marker for COVID-19. Since the number of lymphocytes is reduced and the number of neutrophils is increased, a study has identified the neutrophil-lymphocyte ratio (NLR, the proportion of the neutrophil count to lymphocyte count) to be increased in COVID-19. The NLR was reported to be more increased in severe COVID-19 patients, and thus, the increased NLR could be used as a prognostic criterion for the COVID-19. This study also demonstrated that as the number of lymphocytes reduces, the inflammatory cytokines increase and the disease becomes more critical, which emphasizes the severe inflammatory status as the leading cause of respiratory failure in severe COVID-19 patients (J. Liu et al., 2020) . A study in Wuhan on 99 COVID-19 patients (N. Chen et al., 2020) demonstrated that in severe cases who needed intensive care in the intensive care unit (ICU), the serum levels of inflammatory cytokines, including TNF-α, IP-10, macrophage inflammatory protein 1A (MIP-1A), and MCP-1, were higher than other patients. This emphasizes the role of hyperinflammatory status in the progression and severity of the COVID-19. Also, the first study on 41 COVID-19 patients in Wuhan demonstrated that severe cases had higher levels of inflammatory cytokines including MIP-1A, IL-7, IL-2, IP-10, G-CSF, IL-10, MCP-1, and TNF-α (C. Huang et al., 2020) . Severe COVID-19 patients were also reported to have an increased percentage of custer of differentiation 14 (CD14 + )CD16 + monocytes in their peripheral blood, in comparison to mild COVID-19 patients. The inflammatory CD14 + CD16 + monocytes contribute to the hyperinflammatory status and the cytokine storm by producing multiple inflammatory cytokines (Y. . These findings exhibit the role of the dysfunctional immune response leading to hyperinflammatory status and the cytokine storm in severely ill patients. Identification of the proper function of the immune system against COVID-19 and managing immune dysfunction could pave the way through discovering effective treatments and reducing the mortality rate of COVID-19. To do so, it is critical to understand the exact mechanisms of the innate and adaptive immune response against SARS-CoV-2. Here, we aim to discuss the innate and adaptive immune responses to the SARS-COV-2 based on recent data. Also, we aim to address the dysfunctional immune response and the challenges of the immune response against SARS-CoV-2. To exert an innate immune response against SARS-COV-2, it should be first sensed by the innate immunity as a pathogen. The recognization of the coronavirus family is usually exerted through the identification of the pathogen-associated molecular patterns (PAMPs), viral single-stranded RNA, and viral double-stranded RNA, by pathogen-related receptors of the macrophages. Then, the Toll-like receptors 3 and 7, cytosolic RNA sensor, and RIG1/MDA5 contribute to the identification of the coronavirus. This mechanism leads to the activation of the downstream inflammatory signaling pathways, such as the phosphorylation of nuclear factor-κB (NF-κB), phosphoinositide 3-kinase, mitogen-activated protein kinase, and IFN regulatory factor-3 (IRF-3). Activation of these inflammatory transcription factors finally leads to the induction of innate immune response, production of type 1 interferon (IFN-1), and the release of proinflammatory cytokines such as IL-1β, TNF-α, IL-6, and IL-18 (X. . The macrophage-derived cytokines and type I IFNs also participate to activate the natural killer (NK) cells. NK cells are members of the innate immune system that contribute to the initial immune response against SARS-CoV-2. NK cells exert a major histocompatibility complex (MHC)-independent immune response against SARS-CoV-2 and can restrict the pathogenesis of the virus at the initial steps of infection (Florindo et al., 2020) . The respiratory airway epithelial cells are also among the first immune effector cells that recruit immune cells to the lung tissue by producing immune cytokines and expression of adhesive molecules. Type 1 macrophages (M1), members of the innate immunity with proinflammatory properties, produce antiviral immune response after recognizing the virus. The immune response by macrophages is exerted by the production of multiple immune cytokines, such as type I IFNs, and their phagocytosis (Vabret et al., 2020) . The respiratory mucosa contains many immune effector cells, such as dendritic cells (DCs). DCs inhibit the viral infection as members of the innate immune system. After infection of the respiratory system, DCs start an immediate immune response by producing type I IFNs and IL-6. DCs also stimulate the adaptive immune response by acting as antigen-presenting cells (APCs.) Although the type I IFN-based immune response is initially critical to restrict viral infection, the excess production of type I IFNs by DCs leads to severe inflammation and ARDS in severe patients (Chiappelli et al., 2020) . One of the essential innate immune signals that have a significant antiviral function is IFN-1, including IFN-α, IFN-β, and IFN-λ. APCs, including monocytes and DCs, distinguish the viral antigen on infected cells. Then, APCs introduce the antigen to the helper T (Th) cells. The mechanism of antigen presentation of SARS-COV-2 is not entirely identified yet; however, since the pathogenesis of SARS-COV-2 is similar to SARS-CoV, the same pathway might be applied for the antigen presentation, which is through the MHC-1 (K. Yang et al., 2009) . APCs also produce cytokines that direct the antiviral immune response of the T cells. The cytokines produced by APCs and helper T cells drive the cellular immune response to SARS-CoV-2. Lymphopenia, the reduced number of lymphocytes in the peripheral blood, following mononuclear infiltrations in the COVID-19 autopsy samples, demonstrate the activation of the lymphocytes and their recruitment to the lung tissue to inhibit the infection by SARS-CoV-2. Helper T cells are the directors of the cellular immunity against SARS-CoV-2. In COVID-19 patients, the serum levels of the Th1associated cytokines are reported to be increased. Th1 cells release cytokines, including IFN-γ, TNF-α, and IL-2, that activate the cytotoxic T cells (CTLs). CTLs attack the viral-contaminated cells and destroy them by the producing perforin and granzyme. Also, Th2 cells present the viral antigen to the B lymphocytes, which subsequently produce neutralizing antibodies against the spike (S) protein of the virus. The neutralizing antibodies inhibit the replication of the virus inside the body and produce humoral immunity, which is one of the main concepts for vaccine design against SARS-CoV-2 (X. . Considering SARS-CoV, cellular memory immunity by T cells has been reported to be present for 6 years after SARS (Oh et al., 2011); however, there are no reports of how long can the cellular immunity maintain memory-immunity against SARS-COV-2. Th17 cells are another subgroup of the helper T cells that have been reported to be increased in COVID-19. The production of IL-17, a proinflammatory cytokine, by Th17 cells, promotes the inflammatory response. The exact mechanism of the antiviral function of the Th17 cells, another group of cellular immunity, has not been determined yet. Th17 cells could have antiviral function through the production of inflammatory cytokines; however, further study is required to understand the exact antiviral role of Th17 cells (Prompetchara et al., 2020; . As well as T cells, humoral immunity, mostly through B cells, has a significant role in the induction of adaptive immunity against coronaviruses. The activation of the B cells and the plasma cells leads to the production of the neutralizing antibodies that prevent further contamination by the virus. In most patients, the neutralizing antibodies are present 3 weeks after infection (Bernheim et al., 2020) . Firstly, the B cells start their antibody responses against nucleocapsid (N) of the SARS-CoV-2. Furthermore, the B cells produce antispike (S) antibodies. The anti-SARS-CoV-2 antibodies include two subclasses: IgM and IgG antibodies. SARS-CoV-2-IgM has been reported being present in the serum of the COVID-19 patients 9 days after the onset of the disease. SARS-CoV-2-IgG is present in patient serum 2 weeks after exposure (Totura & Baric, 2012) . Appropriate antiviral antibodies prevent the patient from being reinfected by the virus; however, it has been recently reported that inadequate serum antibody levels could expose the patients to reinfection. Besides, some cases of reinfection have been reported, which questions the humoral-memory immunity against SARS-COV-2 (L. . Further research is needed to be inducted for understanding the accurate immune response mechanism to the SARS-COV-2. SARS-CoV-2-specific T cells and B cells have major roles in the immune response in COVID-19 and thus, must be considered as promising approaches in rational drug and vaccine design against COVID-19. During the cytokine storm, monocytes and Th1 cells produce granulocyte-monocyte colony-stimulating factor (GM-CSF) and IL-6. GM-CSF and IL-6 have a major role in the progression of mild to severe respiratory inflammation and ARDS (X. . A recent systematic review study has exhibited that higher serum levels of IL-6 are associated with poor clinical outcomes and severe pulmonary complications (Russell et al., 2020) . Another important factor that contributes to the dysfunction of the cellular immune response in COVID-19 is the exhaustion of the T cells. T cells separated from COVID-19 patients have an increased expression of programmed death-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), two major surface markers of the T cell exhaustion. The expression of the PD-1 and Tim-3 is associated with disease severity in highly symptomatic patients . The immune system is the main system defending the body against SARS-CoV-2 infection; however, some challenges dampen the antiviral immune against SARS-CoV-2 and lead to dysfunctional immune activity. Both immune-suppressing challenges and severe inflammatory response can lead to dysfunction of the immune system in COVID-19 (Chang et al., 2020) . The insufficient immune response in immune-compromised patients is one of the significant events that prevent the immune system from producing sufficient immunity against the SARS-COV-2. Old patients with multiple comorbidities, cancer patients, patients on immunosuppressive drugs, and other immune-compromised patients are highly susceptible to severe infection with COVID-19. Since their immune system is compromised, they are unable to inhibit the replication of the virus. Thus, SARS-CoV-2 can infect the lower respiratory tract faster and cause pneumonia that can be followed by severe inflammation and ARDS. In conclusion, the insufficient immune response in immune-compromised patients is the underlying cause of higher mortality in old-aged and comorbid patients (Monti et al., 2020) . The second challenge that depletes appropriate antiviral immune response is the capability of the coronaviruses to evade identification by the immune system. This immune-evasion mechanism could ESMAEILZADEH AND ELAHI | 5 be the underlying reason for the prolonged incubation period of the SARS-COV-2 in comparison to influenza or other respiratory viruses. The immune-evasion mechanism of SARS-COV-2 is similar to the immune-evasion mechanism of the SARS and MERS (Park, 2020; Sariol & Perlman, 2020) . Two mechanisms have been identified in SARS and MERS: disturbance in RNA-sensing and type I IFN producing pathways. Accordingly, recent research has reported the production of type I IFN to be decreased in COVID-19 patients (Prompetchara et al., 2020) . Since type I IFN (both α and β subtypes) are important antiviral components of the immune system, the antagonization of the type I interferon signaling in COVID-19 patients reduces the power of the immune system to battle the virus. Also, the type I IFN signature is remarkably disturbed in critically ill patients. It has been demonstrated that SARS-CoV-2 restricts the production of type I IFN through inhibiting IFN-signal transduction pathways, such as IRF-3. This study supports the immune-evasion mechanism of SARS-CoV-2 to be similar to SARS-CoV, through a reduction in the production of the type I IFN (Prompetchara et al., 2020) . The mechanism of action of the IFNs in the COVID-19 is time dependent. In the first stages, IFNs inhibit the progression of the disease by inhibiting the infection of new host cells. However, in the late stages of the disease, IFNs might promote the progression of the disease by inducing the upregulation of ACE-2 by airway epithelial cells, which increases the chance infection of these cells (Vabret et al., 2020) . Another plausible immune evasion mechanism of COVID-19 is the escaping of the virus from the MHC-dependent presentation of its antigens. The MHC-dependent presentation of viral antigens by APCs triggers the adaptive immune response. Thus, the escape of the virus from MHC-dependent antigen presentation restricts the adaptive immune response against SARS-CoV-2, which must be addressed as an immune response challenges against it . The leading mechanism of respiratory failure in COVID-19 is the lung damage caused by exaggerated immune response, severe inflammation, ARDS, and further fibrosis, rather than the direct cytopathic effects of the virus on epithelial cells. The uncontrolled production of the immune cytokines in COVID-19 leads to cytokine storm. Similar to SARS, the cytokine storm is a significant mechanism in the pathogenesis of the SARS-COV-2 in critical ICU patients. The cytokine storm caused by SARS-COV-2 finally leads to the inflammation of the lungs and the formation of hyaluronan . The accumulation of the hyaluronan in the lung leads to the hyaloid membrane formation and further ARDS (Harrison, 2010; . Damaged lung cells and M1 macrophages of the lung produce chemotactic factors that recall innate immune cells and induce an uncontrolled inflammatory response in the lung. Then, the inflammatory cells start an uncontrolled production of proinflammatory cytokines and chemokines. CXCL-8, 9, 10, and CCL-2, 3, and 5 are the major produced chemokines in the process of the cytokine storm. Also, TGFβ, TNF-α, IFN-γ, 6, 12, 18, and 33 , are the cytokines that contribute to the cytokine storm. Also, similar to SARS-CoV1, SARS-CoV-2 induces the expression of IL-6 and IL-8 by its NSP-9 and NSP-10. The upregulation in the expression of IL-6 and IL-8 leads to the progression of mild inflammation to severe inflammation in critical patients (Vabret et al., 2020) . Cytokine storm, the uncontrolled production of immune cytokines, causes lung-tissue damage by activating the immuneinflammatory cells to attack the alveoli and produce fibrotic tissue in the lung, which could finally induce ARDS. Also, the leakage of the fluid to the alveoli and accumulation of the inflammatory exudates lead to respiratory failure (Park, 2020; Wan et al., 2020) . The cytokine storm can also lead to multiple-organ failure that disturbs the function of the kidneys, liver, and heart. Multiple-organ failure is diagnosed by an increase in the level of creatinine, blood urea, AST, ALT, and other end-organ enzymes in severe COVID-19 patients (Tjendra et al., 2020) . According to the destructive role of the cytokine storm in the pathogenesis of the COVID-19, the management of the cytokine storm can reduce lung tissue damage and lead to a better outcome in COVID-19 patients . Multiple strategies, such as the injection of immunomodulatory drugs and mesenchymal stem cells, have applied to inhibit lung damage and multiple-organ failure in severe patients with cytokine storm. Also, targeting inflammatory cytokines could reduce the severity of the cytokine storm. Interventions that lead the immune response through Th2-mediated immune responses are also among other options. These strategies have been discussed in further sections. T cells separated from COVID-19 patients have shown to exhibit T cell exhaustion markers. PD-1 and Tim-3 are two T cell exhaustion markers that were reported to be highly expressed by T cells of the COVID-19 patients. Since T cells are major cellular immunity cells that control the infection of SARS-CoV-2, the exhaustion of the T cells is associated with severe infection and poor antiviral immune response . Identification and inhibition of the mechanisms that contribute to exhaustion of the T cells could increase the efficacy of the immune response against SARS-CoV-2 and lead to improved clinical results. Similar to MERS and SARS, no specific treatment has been approved for COVID-19. The first-line treatment for COVID-19 is supportive treatment, including oxygen therapy, mechanical ventilator support for patients with respiratory failure, antibiotics for prevention of secondary bacterial infection, and body fluid management . Also, some drugs have shown promising results in the treatment of COVID-19. Since the outbreak of the COVID-19, clinicians have started to assess the antiviral functions of existing drugs on this disease, and multiple preclinical and clinical trials have been launched Stebbing et al., 2020) . Viral targeted inhibitors were among the first studied drugs. Adenosine-analogs such as Remdisivir block the viral RNA synthesis process. Also, Remdesivir has shown promising results in the treatment of COVID-19 patients in the clinical setting (Chang et al., 2020) . Other nucleoside analogs such as ribavirin and favipiravir are among the antiviral drugs that could be effective in the treatment of COVID-19 patients; however, no reports have been published about the efficacy of these drugs (Chang et al., 2020) . Immunotherapy uses the potentials of the patient's immune system to fight diseases. Immunotherapy has shown considerable results in the treatment of many diseases such as cancer (Tahmasebi et al., 2019) and viral infections (Boeckh & Corey, 2017) . Amplification and reinforcement of the immune system using immune- in children has been attributed to the low IFN-producing threshold of IFN, which causes the early induction of IFN, and can finally inhibit the SARS-CoV-2 infection. In contrast, the higher mortality rate in elderly patients is at least partly attributed to the higher threshold for IFN production, leading to the delay in IFN production and inadequate immune response. The inhibition of the IFN-producing pathway by the virus and inadequate IFN-production is one of the major challenges of the immune response against COVID-19 (Mosaddeghi et al., 2020) . In an in vitro study, in comparison to many other pathogenic viruses, SARS-CoV-2 was more sensitive to treatment with IFN-α and β (Mantlo et al., 2020) . In the clinical setting, early tripple treatment of COVID-19 with IFN-β1b, lopinavir, and ritonavir, was reported to be more effective than lopinavir-ritonavir alone, inhibit the infection more effectively, and reduce the progression of the disease to severe stages (Hung et al., 2020) . According to in vitro and clinical results supporting the efficacy of treatment with type I IFNs, IFN-based immunotherapy has been considered in clinical trials of COVID-19 patients (Sallard et al., 2020) . Multiple clinical trials are evaluating the efficacy of IFN-α1β, IFN-β, recombinant human IFN-α, IFN-β1a, and IFN-β1b, in the treatment of the COVID-19 in early stages. The clinical trials related to IFN-based immunotherapy have been shown in Table 1 . Also named as IFN-λ (lambda), type III IFNs are involved in the antiviral immune response against viral infections. IFN-λ triggers the Janus kinase (JAK)-STAT signaling pathway, which finally activates inflammatory transcription factors that lead to the expression of IFN-related genes. IFN-λ has shown to induce a robust immune response in chronic viral hepatitis, leading to better clinical outcomes (Phillips et al., 2017) . Considering COVID-19, treatment with IFN-λ could stimulate a stronger immune response against the virus. Thus, Peginterferon IFN-λ, a form of IFN-λ, has been used in COVID-19treating clinical trials (Table 1) Inadequate anti-SARS-CoV antibody levels are associated with increased mortality and a high risk of recurrence (Jacofsky et al., 2020) . Antibody-based treatments are a kind of passive immunotherapy that can improve the immune response and inhibit SARS-CoV-2 infection in COVID-19 patients (Long et al., 2020) . In this section, antibody-based immunotherapies for COVID-19 have been described. Passive immunity in COVID-19 patients can be achieved by the infusion of the SARS-CoV-2 convalescent plasma from recovered patients. Convalescent plasma therapy has been previously used for the treatment of multiple diseases, such as influenza (X.-X. Wu et al., 2015) . It has also shown clinical benefits in patients with SARS (Cheng et al., 2005) and MERS (Ko et al., 2017) . This approach has shown effective results in treating patients with acute and severe COVID-19 patients, as well (Cheraghali et al., 2020; Focosi et al., 2020) . patients with severe COVID-19 with respiratory failure. The patients received concomitant antiviral therapy and IFN-therapy, as well. Plasma-treated patients were reported to have a normal temperature and improved respiratory function after 1 week. Also, 1-12 days following infusion, the respiratory samples were reported to be negative regarding SARS-CoV-2 RT-PCR. In another study, 10 severe Table 1 . Monoclonal antibodies (mAbs) are a group of antibodies that are specifically produced against a specific epitope of an antigen by a specific group of B cells. mAbs are used for the treatment of multiple diseases, including cancers and infectious diseases (Shanmugaraj et al., 2020) . Also, treatment with mAb against previous coronaviruses has shown clinical efficacy in SARS and MERS patients (Modjarrad, 2016) . Since the S1 subunit has an important role in the immunogenicity of coronaviruses, most mAbs target the S1 subunit. Intravenous immunoglobin (IVIG) is a biological product that is produced by gathering polyclonal IgGs from the serum of hundreds of donors. IVIG is routinely used for the treatment of multiple systemic inflammatory diseases, such as autoimmune thrombocytopenic purpura and Kawasaki disease (Jawhara, 2020) . The cytokine storm is the main cause that induces the progression of mild inflammation to ARDS and multiple-organ failure in COVID-19. cytokines is the underlying mechanism leading to severe inflammation in the cytokine storm. Management of the cytokine storm can improve respiratory failure in severe cases with hyperinflammation. This can be achieved using two approaches. First is the inhibition of the inflammatory mechanisms. To inhibit the inflammatory pathways, one could block the pathways of the inflammatory cytokines. Second is the administration of immunosuppressive drugs in severely ill patients with cytokine storm (Bhaskar et al., 2020) . Here, we discuss different approaches to manage the cytokine storm in COVID-19. In response to the cytokines, chemokines, and immune receptors expressed by infected cells and alveolar macrophages, inflammatory immune cells such as macrophages, neutrophils, and monocytes infiltrate into the respiratory tissue. In most cases, the recruitment of these immune cells leads to the clearance of the pathogen through a mild immune response. However, in severe cases, these inflammatory immune cells exert an intense immune response that leads to the uncontrolled production of inflammatory cytokines, which is known as the cytokine storm. IL-1β, IL-6, and TNF-α are the most important cytokines that contribute to the cytokine storm (Tanaka et al., 2016) . The excessive uncontrolled production of IL-6 induces ARDS, leads to the destruction of the alveoli membrane, and causes hemorrhage in the lung. These events finally lead to pulmonary fibrosis. Higher serum IL-6 levels are associated with the severity of the COVID-19 infection. Therefore, blocking IL-6 could reverse the inflammatory mechanism and reduce the severity of COVID-19. Tocilizumab is an anti-IL-6 mAb that can inhibit the inflammatory pathway induced by IL-6. The appli- (Table 1) . IL-1β is a proinflammatory cytokine that has an important role in the progression of respiratory inflammation in many viral infections (Conti et al., 2020) . In response to alveolar infection by SARS-CoV-2, macrophages secrete IL-1β, which induces fever and stimulates the mechanisms that lead to respiratory fibrosis in the lung. Higher levels of IL-1β are associated with the severity of COVID-19 infection in critically ill patients (Price et al., 2020) . Thus, inhibition of the IL-1β in severe stages of the disease could be an effective approach to reduce the progression of the cytokine release syndrome and ARDS. Anakinra is a recombinant IL-1 receptor antagonist that has been considered in the clinical trial of COVID-19 (NCT04341584). Canakinumab is another mAb against IL-1β that has been proposed to be investigated in the COVID-19 clinical trials (Table 1) . TNF-α is an inflammatory mediator that is produced by the innate immune cells in response to the SARS-CoV-2. TNF-α is among the first cytokines that are produced by the innate immune cells in COVID-19 and has shown to have an important role in the induction of the immune response against coronaviruses. This effect is conducted by inducing the recruitment of the leukocytes to the infection site and differentiation of the DCs (Price et al., 2020) . According to the role of the TNF-α in the progression of the cytokine storm, inhibiting TNF-α could be considered as a promising approach to reduce the hyperinflammation in severe COVID-19 infection. XPro1595 is a soluble TNF-α-neutralizing protein that inhibits the interaction between soluble TNF-α and its receptor. XPro1595 has shown appropriate clinical results in chronic inflammatory disorders, such as Alzheimer's disease, and is being investigated in the clinical trial of COVID-19 (Table 1) . IL-17 is an inflammatory cytokine that has shown to have a sig- IFN-γ is a soluble cytokine and a member of the type II interferons. Produced by NK, CD4+, and CD8+ lymphocytes, IFN-γ exerts an important role in the immune response against viruses. However, the excessive production of IFN-γ promotes the progression of severe inflammation and lung tissue damage (L. Chen et al., 2018; Meissner et al., 2010) . The inhibition of IFN-γ has previously shown to alleviate acute lung injury in H1N1 influenza in in vivo studies (B. Liu et al., 2019) . In clinical studies, IFN-γ has shown to be an important biomarker promoting the pathogenesis of ARDS and acute lung injury (Spadaro et al., 2019) . Thus, the inhibition of IFN-γ, using anti-IFN-γ antibodies, could be considered as an immunotherapeutic method to inhibit the progression of the ARDS in severe COVID-19 infection. An example is the application of Emapalumab, an anti-IFN-γ Ab, for the treatment of COVID-19 in a clinical trial (NCT04324021). As members of the innate immune system, complements are inactive proteins in the serum. After being activated, the complement system assists the antimicrobial function of the immune system and stimulates the activation of neutrophils. Although complements are not cytokines, some members of the complement system have some immune functions that are similar to cytokines. Through these mechanisms, the complement system exerts an important role in the progression of the inflammation (Risitano et al., 2020) . C3 and C5 are two major members of the complement system. Inhibition of the ESMAEILZADEH AND ELAHI | 13 complement system, using avdoralimab, zilucoplan, and ravulizumab, as C5 inhibitors, and AMY-101, as a C3 inhibitor, has been considered in the clinical trials of COVID-19 (Table 1) . Considering the immunomodulatory effects of corticosteroids, dexamethasone, and other oral/IV corticosteroids, were among the first drugs that were proposed for the treatment of cytokine storm in severe COVID-19. Corticosteroids exert their anti-inflammatory effect by inhibiting the expression of proinflammatory transcription factors in the nuclei of inflammatory cells (Ramesh et al., 2015) . The application of dexamethasone is not indicated in mild to moderate patients; however, in severe COVID-19 infection with hyperinflammatory status, the injection of corticosteroids could alleviate the inflammation and ARDS (Azimi et al., 2020) . Multiple clinical trials are investigating the efficacy of treatment with steroids in severe COVID-19, which are described in Table 1 . As immune suppressor drugs, corticosteroid application is accompanied by some known side effects, such as vascular necrosis and diabetes, which must be taken into consideration . The antibody-based immunity against SARS-CoV-2 can be achieved by both passive and active immunotherapeutic methods. Plasma therapy and treatment with IVIG are two examples of passive immunotherapy. Considering the challenges of treatment with passive immunotherapy, such as limited resources and high cost, active immunotherapy using antiviral vaccines has been considered from the first steps of the pandemic (Roback & Guarner, 2020) . Here, we aim to discuss the recent progress in the production of SARS-CoV-2specific vaccines as novel immunotherapeutic approaches. Bacille Calmette-Guérin (BCG) is a routinely used vaccine for protection against tuberculosis. In addition to the long-time active immunization against tuberculosis, BCG vaccination has shown nonspecific immune response against other diseases, such as viral upper respiratory infections. Possibly, this protection is exerted by a nonspecific innate immune response to BCG (Miller et al., 2020) . To investigate the probable association between BCG vaccination and COVID-19 mortality, Shet et al. (2020) used a simple log-linear regression model. This study demonstrated that BCG-vaccinating countries had shown much lower COVID-19associated mortality in comparison with non-BCG-using countries (Shet et al., 2020) . These data demonstrated the protective role of BCG vaccination against COVID-19 through a nonspecific immune response. Thus, BCG vaccination could be introduced as nonspecific immunotherapy to induce nonspecific innate immune response against COVID-19; however, further research is required to evaluate the efficacy of this approach. Several clinical trials have been started to compare the infection and mortality in BCGvaccinated individuals compared to non-vaccinated individuals (Table 1) . Cell therapy is an immunotherapeutic approach that has recently gained much attention for the treatment of viral respiratory infections, as well as cancers (Elahi et al., 2018) . Showing therapeutic efficacy against other viral respiratory infections, cell therapy has been developed as an attractive treatment strategy in COVID-19 (J. Du et al., 2020) . In this section, we describe different cell therapy methods developed for the treatment of COVID-19. (J. (Bari et al., 2020) . Thus, similar to the transplantation of the MSCs, treatment with MSC-derived secretomes has also been suggested as a potential therapeutic approach in COVID-19. The secretome can be administered in two ways, first is the inhaled spray form of the secretome, and the second is the intravenous prescription (Deffune et al., 2020) . Based on this, some clinical trials have been launched to assess the safety and efficacy of MSC-derived secretome in the treatment of COID-19 (Table 1) . NK cells are a subset of lymphocytes and members of the innate immunity. NK cells are among the first immune components contributing to the initial immune response against virus-infected and cancer cells (Hammer et al., 2018) . After being activated by macrophage-derived cytokines and type I IFNs, NK cells attack the virus-infected cells. The most specific characteristic of the NKderived immune response is its MHC-independency and rapidity (Paul & Lal, 2017 Chimeric antigen receptor (CAR) is a genetically engineered receptor that is widely applied in the treatment of multiple cancers (Tahmasebi et al., 2019) . Engineered cells expressing CAR can specifically target the antigen-expressing cells. Since NK cells have an important role in the antiviral immune response against SARS-CoV-2, engineered CAR NK cells have been suggested as a novel approach for the treatment of COVID-19. ACE-2 is the antigen that could be utilized for designing CAR NK cells against SARS-CoV-2. NCT04324996 is a phase I/II clinical trial that has been started to assess the therapeutic efficacy of universal Off-the-shelf NKG2D-ACE2 CAR NK cells in the treatment of COVID-19 pneumonia. Similar to MSCs, the virus-specific T cell culture media contain T cell-derived extracellular exosomes that include antiviral materials (Golchin et al., 2020) . The T cell-derived extracellular exosomes could improve the antiviral immune response by activating immune cells (Fu et al., 2019) . Thus, SARS-CoV-2-specific T cell-derived exosome transfer is a novel therapeutic method for the treatment of COVID-19. Corresponding clinical trials have been launched to investigate the therapeutic efficacy of adoptive cell therapy in COVID-19, which have been described in Table 1 . Lymphopenia is one of the most common laboratory signs in COVID-19. In addition to the reduction in the number of cytotoxic CD8 + T cells, two studies have also reported the exhaustion of the T cells in COVID-19 patients. PD-1 is an exhaustion marker of the T cells. The higher levels of PD-1 expression by T cells is associated with higher exhaustion of these cells. Exhausted T cells have a reduced antiviral function and thus have lower antiviral potency. Also, Tim-3, another T cell exhaustion surface marker, is highly expressed by the T cells in COVID-19 patients . From this standpoint, some clinical trials have targeted the inhibition of PD-1 and Tim-3 in the treatment of COVID-19. Clinical trials investigating the efficacy of PD-1 blockade in COVID-19 patients are described in Table 1 . NKG2A, an exhaustion marker expressed by NK cells and cytotoxic T lymphocytes, has been reported to be upregulated in severe COVID-19 patients. The upregulated expression of NKG2A reduces the production of proinflammatory cytokine by NK cells and T lymphocytes . Inhibition of the NKG2A could also be considered in the treatment of the COVID-19 patients, which has been discussed in further sections. By producing immune-stimulating cytokines (CD4 + cells) and attacking the virus-infected cells (CD8 + ) cells, T cells exert their immune response against SARS-CoV-2 (Bernheim et al., 2020) . As members of the innate immune system, type 1 DCs (DC-1) exert their antiviral immune response by producing IL-6 and type I IFN, and acting as APCs (Vabret et al., 2020) . DCs also activate the NK cells by expressing NKG2D (Draghi et al., 2007) . Moreover, the hypersecretion of IL-6 by DC-1 cells is considered as one of the important mechanisms that contribute to the progression of respiratory inflammation and lung tissue damage in ARDS (Rajaei & Dabbagh, 2020) . To manage the hyperinflammatory process in severe COVID-19 patients, it could be useful to inhibit the proinflammatory effects of DCs, either by application of DC-blocking agents or using engineered DCs (Lega et al., 2020) . Two types of macrophages have been identified. Type 1 macrophages (M1) with proinflammatory functions, and type 2 macrophages (M2) with anti-inflammatory properties. In COVID-19, M1 macrophages contribute to the severe inflammation by secreting proinflammatory cytokines, such as IL-6 and IL-1β (Merad & Martin, 2020) . To suppress the hyperinflammatory condition, macrophages can be modified in two ways. The first method is the modulation of the M1 macrophages to secrete lower levels of proinflammatory cytokines. The second approach could be the application of M2 macrophages to suppress the inflammation of the lungs (Lega et al., 2020) . Considering the application of macrophages for the treatment of COVID-19 could be considered in further research. Two main challenges reduce the optimal antiviral immune response of the lymphocytes in COVID-19. First is lymphocytopenia which is decrease in the number of T and NK cells. Second is the exhaustion of T cells which is identified by overexpression of NKG2A, PD-1, and Tim-3, on NK cells and cytotoxic T lymphocytes Zheng et al., 2020) . Immune checkpoint inhibition is a developing approach that has been widely studied in the concept of cancer treatment (Decazes & Bohn, 2020) . Here, we aim to review recent data on checkpoint inhibition as a developing method for the treatment of COVID-19. PD-1 and Tim-3 are surface markers of T cell exhaustion expressed by exhausted T lymphocytes . Previous studies have reported the upregulated expression of PD-1 and Tim-3 on T lymphocytes in COVID-19 ICU-admitted patients compared to non-ICU patients. Thus, the reduction in the number of lymphocytes (lymphopenia) is accompanied by the upregulated expression of PD-1 and Tim-3 on residual T lymphocytes in severe COVID-19 cases . Inhibition of the PD-1 could reduce the exhaustion of the lymphocytes and increase the immune response potency in COVID-19 patients (López-Collazo et al., 2020) . Therefore, inhibition of PD-1 has been considered in the clinical trial design in COVID-19 that has been described in Table 1 . Higher levels of proinflammatory cytokines have been shown to be associated with higher PD-1 and Tim-3 expression by T cells in severe COVID-19 cases. This supports the role of the cytokine storm in the exhaustion of T lymphocytes (Moon, 2020) . Therefore, management of the cytokine storm not only reduces lung tissue damage, but also leads to an improved immune response by limiting T cell exhaustion. NKG2A is an immune-inhibitory receptor expressed by NK cells and cytotoxic T lymphocytes. The higher expression of NKG2A is associated with lower immune functionality of the NK and cytotoxic T cells, which is conducted by reducing the capability of these cells to secrete granzymes and release cytokines (Antonioli et al., 2020) . Considering the immune-suppressive state in tumors, inhibiting NKG2A has shown to overcome the immune resistance by increasing the immune function of the NK cells (Kamiya et al., 2019) . Serum samples separated from COVID-19 patients have also shown upregulated expression of NKG2A by NK and cytotoxic T cells. The upregulated expression of NKG2A was associated with lower secretion of TNF-α, IL-2, IFN-γ, granzyme B, and CD107a . As a result, the upregulated expression of NKG2A is sought to have an important role in the compromised immune response against SARS-CoV-2 in COVID-19 patients. Therefore, inhibition/downregulation of NKG2A could reduce the exhaustion of T cells and produce a stronger immune response by T and NK cells. JAK is a member of the intracellular cytokine signaling pathway, named as the JAK-STAT pathway. JAK stimulates the production of proinflammatory cytokines by mediating the phosphorylation of the STAT family. Phosphorylation of the STAT leads to the production of several proinflammatory cytokines, including IL-6. The uncontrolled production of the proinflammatory cytokines leads to severe inflammation and cytokine storm, which causes severe damage to the lung and develops multiorgan failure. Accordingly, inhibition of the JAK could reduce the production of proinflammatory cytokines and can thus be suggested in the treatment of the cytokine storm in severe COVID-19 patients (Favalli et al., 2020) . Several JAK-inhibitors could be used in the treatment of COVID-19. Recent literature has introduced Baricitinib, a JAK inhibitor, as a potential treatment for acute viral pneumonia in COVID-19. As well as reducing inflammation by inhibiting JAK, Barticinib limits the entrance of the virus to the host cells by inhibiting adaptor-associated protein kinase 1 receptor . Thus, barticinib could be introduced as a therapeutic agent to be studied in further clinical trials of COVID-19. At the first stages of COVID-19, SARS-CoV-2-associated reduction in type I IFN is mediated by the inhibition of the JAK-STAT pathway. Thus, time must be noted in the prescription of JAKinhibitors. Treatment with JAK-inhibitors in the first stages can worsen the infection by reducing the production of type I IFN and limiting its antiviral potency. However, treatment with JAKinhibitors in severe cases with cytokine could be beneficial by reducing proinflammatory cytokines (Fleming, 2016) . Currently, some clinical trials have been launched to evaluate the efficacy of JAK inhibitors in the treatment of COVID-19 that have been discussed in Table 1 . GM-CSF is a glycoprotein secreted by monocytes, macrophages, and Th1 cells. GM-CSF acts on the bone marrow and stimulates the production of granulocytes (Merad & Martin, 2020) . It also increases the migration of the neutrophils and monocytes to the inflammatory site. GM-CSF, in companion with IL-6, contributes to the progression of the severe inflammation during ARDS. The inhibition of GM-CSF has previously shown to improve ARDS (Goodman et al., 1999) . From this standpoint, inhibiting GM-CSF could also reduce the severity of ARDS and lung tissue damage in COVID-19. Multiple clinical trials have considered GM-CSF blockade using lenzilumab, otilimab, gimsilumab, mavrilimumab, and sargramostim, as a potential therapeutic method in COVID-19 (Table 1) . 4.6.5 | CCR5 inhibition C-C chemokine receptor type 5 (CCR5) is a chemokine receptor for CCL3, CCL4, CCL5, and CCL3L1. CCR5 is expressed by multiple leukocytes, including macrophages, T cells, and DCs (Wei & Nielsen, 2019) and has shown to have an important role in the direction of the leukocytes to the inflammatory site. Therefore, CCR5 is one of the major checkpoints promoting inflammation in COVID-19 (Merad & Martin, 2020) . Inhibiting CCR5 is one of the recently proposed methods to inhibit the severe inflammation in COVID-19. To the best of our knowledge, a CCR5-specific mAb, lenrulimab, is being used to inhibit CCR5 in two recent clinical trials (NCT0434365 and NCT04347239). VEGF is a subset of the growth factor family that contributes to the angiogenesis, formation of new vessels in the tissue, and induction of the migration and mitosis of the endothelial cells (Niu & Chen, 2010) . Recent studies have reported the serum levels of VEGF to be increased in severe COVID-19 patients (X. Yang et al., 2020) . VEGF contributes to the progression of acute lung injury by increasing the permeability of the vessels that leads to respiratory edema, a major factor in ARDS. Thus, VEGF is a potent therapeutic target in ARDS and acute lung injury in COVID-19. Clinical trials have astarted to investigate the therapeutic efficacy of VEGF-inhibition, using a VEGF-specific mAb, Bevacizumab (Table 1) . CD14 is expressed on the surface of the macrophages and monocytes. As part of the innate immune system, CD14 contributes to the recognition of the PAMPs. Since macrophages play a major role in the inflammatory process, inhibition of CD14 attenuates macrophage-associated signaling pathways, and suppresses inflammation (da Silva et al., 2017) . Thus, CD14 could be considered as a potential therapeutic target in COVID-19-associated inflammation and ARDS. IC14, an anti-CD14 mAb, can appropriately inhibit CD14, and thus, has been used to inhibit CD14 in corresponding clinical trials (Table 1) . There is a proven interaction between inflammation and coagulation. An example is the increased risk of diffuse intravascular coagulation in severe sepsis. Chronic severe inflammation increases the chance of developing intravascular thrombosis. Proinflammatory cytokines, mostly IL-6, stimulate coagulation markers such as the tissue factor, and suppress anticoagulatory factors (Levi & van der Poll, 2010) , which lead to the increased production of thrombin and fibrin. On the other hand, coagulatory factors can increase inflammation by acting on specific cell receptors. Coagulopathy has also shown to have an important role in the progression of multiple-organ failure by causing small thrombosis in different organs (Levi & van der Poll, 2005) . Considering the two-way crosstalk between coagulation and inflammation, inhibiting coagulation could reduce mortality in COVID-19 by decreasing the risk of intravascular small thrombosis, as well as attenuating the severe inflammation. Prophylaxis of coagulation is being studied in COVID-19 clinical trials (Table 1) . Low-dose radiotherapy has shown to have anti-inflammatory effects and is being used for the treatment of multiple chronic inflammatory disorders (Arenas et al., 2012) . Low-dose ionizing radiation exerts its anti-inflammatory effect by acting on the endothelial cells. Ionizing radiation also increases the adhesion of the monocytes to the wall of the vessels (Schröder et al., 2018) . In conclusion, low-dose radiotherapy could be used to suppress the inflammation in COVID-19. Corresponding clinical trials regarding anti-inflammatory radiation therapy of COVID-19 have been described in Table 1 . Immune-enhancing therapies can improve the antiviral immune response in the early stages of the infection with SARS-CoV-2. IL-2 is an immune-stimulating cytokine that is produced by the helper and cytotoxic T cells. 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Immunobiology and immunotherapy of COVID-19: A clinically updated overview The authors would like to acknowledge COVID-19 patients and health workers (physicians, nurses, laboratory staff, etc.) around the world for their precious efforts fighting COVID-19.