In the setting of other viral infections, the efficacy of anti\PD\1 (pembrolizumab) has been evaluated in a small cohort of patients with John Cunningham virus infection. 119 Targeting PD\1 and possibly other ICs in COVID\19 patients could be beneficial in releasing the brake of T\cell exhaustion to induce more potent and sustained antiviral responses mediated by effector T cells and cytotoxic CD8+ T cells, and the development of functional memory T cells for long\term immunity. 89 , 120 Four clinical trials have been designed to assess the safety and therapeutic efficacy of anti\PD\1 monoclonal Thymosin β4 antibody (mAb) in patients with COVID\19 (“type”:”clinical-trial”,”attrs”:”text”:”NCT04268537″,”term_id”:”NCT04268537″NCT04268537, “type”:”clinical-trial”,”attrs”:”text”:”NCT04333914″,”term_id”:”NCT04333914″NCT04333914, “type”:”clinical-trial”,”attrs”:”text”:”NCT04356508″,”term_id”:”NCT04356508″NCT04356508 and “type”:”clinical-trial”,”attrs”:”text”:”NCT04413838″,”term_id”:”NCT04413838″NCT04413838) (Table ?(Table1).1). Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti\inflammatory drugs to improve antiviral T\cell responses against SARS\CoV\2. models showed that SARS\CoV\2\infected pneumocytes and alveolar macrophages prompted the release of proinflammatory cytokines and antiviral IFN (type I and III) at low levels. 23 , 24 Lung autopsy from a COVID\19 case provided important insights into the distribution of immune cell infiltrates in the lungs; alveolar exudate showed moderate levels of macrophages and low levels of neutrophils, while interstitial compartment showed infiltration of T cells and monocytes, but not B cells. 25 Other post\mortem findings from 38 patients who died with COVID\19 showed infiltration of macrophages in alveolar lamina and lymphocytes in pulmonary interstitium. 26 Lymphopenia observed in the circulation of COVID\19 patients, particularly in those with severe disease, may occur as a result of lymphocyte infiltration and sequestration in the lungs. 27 , 28 Moreover, pulmonary influx of immune cells could also potentially justify elevated neutrophil\to\lymphocyte ratios recorded in COVID\19 patients and presented as a biomarker for disease severity and organ failure, 28 due to imbalances in immune cell infiltrates in the lungs; however, concrete evidence is warranted to support it. Liao Thymosin β4 and and higher levels of inflammatory cytokines including IL\6, IL\8 and IL\1 in BALF, reflecting the hyperinflammatory state in the lungs of these patients. 29 Chua expression is correlated with expression, and showed that LAMC1 these samples exhibit higher expression levels of and genes in patients with severe disease, which could promote T\cell recruitment. 30 These latter findings demonstrated that epithelial cell/alveolar damage in COVID\19 patients could be driven by the crosstalk between epithelial and immune Thymosin β4 cells accompanied by a proinflammatory environment, potentially giving rise to a positive feedback loop that augments inflammation and tissue destruction. 30 In addition, the massive infiltration of immune cells into the airways of COVID\19 patients could significantly contribute to acute lung injury and bacterial pneumonia. 10 IMMUNE RESPONSES TO SARS\CoV\2 The arsenal of innate and Thymosin β4 adaptive immunity is mostly capable of eliciting adequate antiviral immune responses in mild and moderate cases of COVID\19 (Figure ?(Figure1A).1A). Indeed, the co\ordination between innate and adaptive immune responses during early stages of SARS\CoV\2 infection is essential to control viral dissemination. 31 Moreover, adequate T\cell counts and sufficient T\cell activation/clonal expansion have Thymosin β4 been recorded in COVID\19 convalescent patients, 32 , 33 implying the importance of T\cell\mediated immunity in recovery and disease resolution. T\cell\dependent protective roles encompass systemic antiviral immune responses and Th\cell\mediated activation of B cells, while CTLs have prominent roles in the elimination of virus\infected cells. 34 Dendritic cells (DCs) and macrophages can phagocytose virus\infected cells to initiate T\cell responses via antigen presentation. 35 Subsequently, CD4+ T cells stimulate B cells for the production of viral\specific antibodies, and cytotoxic CD8+ T cells to target virus\infected cells. In addition, recognition of viral pathogen\associated molecular patterns (PAMPs), such as viral RNA or damage\associated molecular patterns (DAMPs) from host cells, by pattern recognition receptors (PRRs), including RIG\I\like receptors (RLRs) and Toll\like receptors (TLRs), initiates an inflammatory response and leads to elevated secretion of inflammatory cytokines and chemokines, such as interferon\gamma (IFN\), interleukin (IL)\6, monocyte chemo\attractant protein\1 (MCP1) and C\X\C motif chemokine 10 (CXCL10). 19 Open in a separate window Figure 1 T\cell responses against SARS\CoV\2. SARS\CoV\2 recognizes cells expressing ACE2 receptor including epithelial cells and macrophages. In normal immune environment, infected epithelial cells degrade viral particles and present them to cytotoxic CD8+ T cells (CTLs). CTLs detect viral protein through classical TCR\MHC I interaction, release cytotoxic granules, including granzyme B and perforin, and eliminate infected cells. Additionally, macrophages detect SARS\CoV\2 via ACE2 receptor and present the virus\derived peptides to CD4+ T cells (Th0) via TCR\MHC II interaction. Once exposed to antigen, Th0 cells polarize primarily towards Th1, leading to the release of IFN\ to eliminate the virus, and Th2 to trigger humoral\mediated immune responses and antibody secretion against SARS\CoV\2 virus (A). In incompetent immune environment, SARS\CoV\2 recognizes epithelial cells or macrophages via ACE2 receptor. Viral RNA will.
In the setting of other viral infections, the efficacy of anti\PD\1 (pembrolizumab) has been evaluated in a small cohort of patients with John Cunningham virus infection