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In view of dysregulated immune response, cytokine storm and inflammation-induced lung damage in severely ill COVID-19 patients, we propose that CD4+CD25+FoxP3+ regulatory T cell-based therapies could be considered for the patient management.
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Potential of regulatory T-cell-based
therapies in the management of severe
COVID-19
To the Editor:
Cytokine storm, inflammation-mediated severe lung damage and defective haemostasis are the main
underlying reasons for morbidity and mortality in coronavirus disease 2019 (COVID-19) patients [1].
Several immunotherapies that target various inflammatory processes have been successfully used in
COVID-19 patients and many other strategies are under evaluation [2, 3]. However, in view of
dysregulated immune responses in severe COVID-19 patients, we suggest that CD4
+
CD25
+
FoxP3
+
regulatory T-cell (Treg)-based strategies could be considered for patient management.
Vigorous antimicrobial responses triggered against the pathogen can be detrimental to the host due to
collateral tissue damage. Therefore, regulatory mechanisms, and in particular Tregs, are in place to ensure
that inflammation is kept in check. Tregs are either thymus-derived or induced in the periphery and are
classically known for stimulating immune tolerance, and preventing autoimmune and inflammatory
diseases [4]. Tregs inhibit the activation of both innate and adaptive immune cells via inhibitory surface
molecules (like cytotoxic T-lymphocyte antigen-4 (CTLA-4) and lymphocyte-activation gene-3) and
secretion of immunosuppressive cytokines (interleukin (IL)-10, transforming growth factor-βand IL-35).
Both Treg subsets are equally important to prevent inflammation-induced tissue damage during acute
infections and to promote tissue repair, which is particularly shown in the influenza infection model [4, 5].
The current evidence suggests that the level of peripheral Tregs is prominently reduced in severely ill
COVID-19 patients compared with mild patients [69]. Though the reasons for reduced frequency of
Tregs in peripheral blood are not completely understood, one of the possibilities is that Tregs might have
migrated to the lungs to prevent tissue damage. Detailed investigation of Tregs in the lung tissues of severe
COVID-19 patients and their molecular signatures would provide insight on these questions. However, in
silico analyses performed on the transcriptomic data of CD4
+
T-cells from the COVID-19 patients
bronchoalveolar lavage suggest that IL2 transcripts were reduced in severe cases compared with mild cases
[10]. Therefore, reduced IL2 would lead to enhanced apoptosis of Tregs and is also confirmed by reduced
levels of FoxP3. Moreover, severe COVID-19 patients have increased levels of soluble IL-2R (CD25) [68],
probably due to inflammation-induced enhanced proteolytic cleavage of cell surface CD25. This soluble
CD25 could potentially interfere with IL-2 bioavailability and signalling, and hence might further promote
apoptosis of Tregs. It has also been shown that Middle East respiratory syndrome coronavirus could infect
T-cells [11] and hence, a direct effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
on the biology of Tregs cannot be ruled out.
Considering the importance of Tregs in immune homeostasis, reduction in the levels of Tregs could be
one of the reasons for the hyperactivated immune system and damaged lungs in severe COVID-19
patients. It is worth noting that depletion of Treg from the mice infected with murine coronavirus lead to
increased mortality with acute encephalitis, thus highlighting the protective nature of Tregs during acute
coronavirus infection [12]. It should also be noted that obesity is one of the risk factors for COVID-19,
and data from obese subjects and pertinent animal models have shown that Tregs in the circulation and
visceral adipose tissues are decreased compared with those in lean subjects, and consequently there is a
higher state of inflammation and insulin resistance [13, 14].
@ERSpublications
In view of dysregulated immune response, cytokine stormand inflammation-induced lung damage
in severely ill COVID-19 patients, we propose that CD4
+
CD25
+
FoxP3
+
regulatory T-cell-based
therapies could be considered for patient management https://bit.ly/3eKqWPo
Cite this article as: Stephen-Victor E, Das M, Karnam A, et al. Potential of regulatory T-cell-based
therapies in the management of severe COVID-19. Eur Respir J 2020; 56: 2002182 [https://doi.org/
10.1183/13993003.02182-2020].
https://doi.org/10.1183/13993003.02182-2020 Eur Respir J 2020; 56: 2002182
||
AGORA
CORRESPONDENCE
Given the dysregulated immune response in severe COVID-19 patients, we propose that Tregs have
therapeutic potential in patient management. Adoptive transfer of ex vivo expanded polyclonal Tregs has
recently been used to treat autoimmune and inflammatory diseases [15]. But polyclonal Treg therapy is
time consuming, requiring nearly 2 weeks to expand sufficient quantities of viable clinical-grade Tregs for
immunotherapy. However, unlike autoimmune diseases, COVID-19 patients need an instant therapy to
prevent morbidity and mortality. Therefore, adoptive transfer autologous polyclonal Treg therapy is not a
viable option in COVID-19 patients. Also, the approach is not economically feasible for an infectious
disease. Alternatively, allogeneic human leukocyte antigen-matched umbilical cord-derived Tregs are under
exploration for inflammatory conditions (ongoing clinical trials registered at ClinicalTrials.gov:
NCT02932826 and NCT03011021) (figure 1) [16]. In view of the drawbacks of autologous Treg therapy,
allogeneic-matched cord Tregs could be considered for severe COVID-19 patients. Of late, two COVID-19
patients with acute respiratory distress syndrome (ARDS) were treated twice or thrice with allogeneic, off-
the-shelf, cord-blood derived, ex vivo expanded Tregs (1 × 10
8
cells per dose). The Treg therapy was
associated with rapid decline in the various inflammatory mediators including IL-6, TNF-α, IFN-γ, IL-8
and IL-12 [17].
Another strategy is to boost Tregs in vivo. Low-dose IL-2 has been used to specifically induce Treg
expansion in vivo in type 1 diabetes, and other autoimmune and inflammatory diseases [18]. The high
affinity of CD25 towards IL-2 would lead to selective Treg expansion. But severe COVID-19 patients
display increased levels of soluble IL-2R [68] that could potentially scavenge IL-2. Other reports have
demonstrated that severe COVID-19 patients have increased IL-2 levels [1] and despite having higher IL-2,
Tregs were lower in severe COVID-19 patients. All these arguments suggest that low-dose IL-2 therapy
might not be beneficial in COVID-19 patients. Nevertheless, a clinical trial is planned with low-dose IL-2
for acute respiratory distress syndrome related to COVID-19 (trial NCT04357444 registered at
ClinicalTrials.gov). Data from this trial will provide valuable information on the feasibility of this strategy
not only for COVID-19 but also for other acute viral diseases. Other Treg expansion strategies, like IL-2
complexed with monoclonal antibodies to selectively trigger Treg activation [19] or to induce STAT5
phosphorylation and Treg expansion [20], have been explored in pre-clinical models. But they have yet to
be tested in clinic and in view of their unproven efficacy in patients, it is too risky to use them in
COVID-19 patients.
CD4
Treg
CD28
CD28
CD80/86
CD80/86
CD25 Allogenic cord blood Treg
Low-dose IL-2 ??
IL-2
Severe COVID-19 Potential of Treg-based therapeutic strategies in the
management of COVID-19
Immune
cell activation,
inflammation
Immune
cell activation,
inflammation CTLA-4-Fc
(Abatacept)
Immune
cell activation,
inflammation
Immune
cell activation,
inflammation
IL-6
IL-1β
TNF-α
Soluble
CD25
APC
Treg
Treg Treg
CD4
APC
FIGURE 1 Potential of regulatory T-cell (Treg)-based therapies in the management of severe coronavirus disease 2019 (COVID-19). Tregs and their
functions are compromised in severe COVID-19 patients, engendering unrestrained immune cell activation. Dysregulated antigen-presenting cells
(APCs) insinuate tissue inflammation and immunopathology by secreting inflammatory cytokines and activating a T-cell-dependent immune
response. We suggest that either adoptive transfer of allogenic Tregs or use of Treg-derived molecules like cytotoxic T-lymphocyte antigen
(CTLA)-4 (abatacept) might block the activation of APC and costimulatory pathways. Such therapies have the potential to curtail tissue
inflammation and immunopathology, leading to better management of COVID-19 patients. IL: interleukin; TNF: tumour necrosis factor.
https://doi.org/10.1183/13993003.02182-2020 2
CORRESPONDENCE
In view of various shortcomings with either adoptive Treg therapy or in vivo Treg expansion strategies,
therapy with Treg-derived immunoregulatory molecules, in particular CTLA-4, might hold the potential
for controlling inflammation in severe COVID-19 patients (figure 1). At cellular level, CTLA-4 interacts
with B7 family members (CD80 and CD86) on innate cells. Through trans-endocytosis and degradation of
B7 molecules inside CTLA-4-expressing cells, CTLA-4 reduces co-stimulatory signals for T-cells [21]. The
recombinant Fc-fused CTLA-4 protein abatacept has been used for several years for the immunotherapy of
systematic autoimmune diseases. Though our knowledge on the mechanisms of this fusion protein is still
incomplete, current literature suggest that by interacting with B7 molecules on antigen-presenting cells,
abatacept interferes with CD28-mediated T-cell signalling and activation [22]. Abatacept might also affect
the activation of innate cells, such as monocytes and dendritic cells, and enhance Tregs, though data on
the Treg function are limited and conflicting [23, 24].
While data is not available regarding abatacept therapy in COVID-19 patients, recent longitudinal
observational studies on the incidence of COVID-19 in abatacept-treated patients provide a pointer towards
its therapeutic potential in severely ill COVID-19 patients. An epidemiological survey performed in the large
tertiary hospital in Barcelona (Spain) indicated that abatacept-treated patients (42 patients from a cohort of
959 patients treated with biological and synthetic disease-modifying anti-rheumatic drugs (DMARD))
exhibited the lowest frequency of COVID-19-compatible symptoms [25]. Similar data were also obtained
from a hospital in Madrid (Spain), where it was noted that none of the 27 abatacept-treated patients (among
802 DMARD-treated patients) were admitted to hospital with COVID-19 symptoms [26]. Furthermore,
among 779 biological DMARD-treated patients from Siena (Italy), only two tested positive for COVID-19
and notably none of the 55 abatacept-treated patients in this cohort experienced COVID-19 [27].
Although these observations are from small cohorts and it is possible that the patients were practicing
strict social distancing, the data on abatacept-treated patients are not surprising in view of its documented
clinical benefits in autoimmune diseases [28] and the mechanisms of action of CTLA-4 to mitigate
inflammatory responses.
Various immunotherapies that target the cytokine storm and prevent lung damage have gained
prominence in the management of severe COVID-19 patients. Among the Treg-based therapeutic
approaches, CTLA-4-based therapies appear to be attractive to overcome the hyperinflammatory state of
severely ill COVID-19 patients. Clinicaltrials.gov registry shows that 47 studies are registered for the
evaluation of tocilizumab (a humanised monoclonal antibody to IL-6 receptor α)/sarilumab (a fully
human monoclonal antibody to IL-6 receptor α) in COVID-19 patients and 14 studies are registered for
anakinra (an IL-1 receptor antagonist). However, just a single Phase 2 clinical trial has been registered
recently for abatacept therapy in COVID-19 patients (trial NCT04472494 registered at ClinicalTrials.gov).
Initial clinical trials mainly focused on the management of the cytokine storm and in particular, the role
of IL-6 and IL-1β. Data on the Tregs in COVID-19 patients were also scarce during the early period of the
COVID-19 pandemic. These points may explain why abatacept is yet to be considered for the management
of COVID-19 patients, apart from the recently registered clinical trial (NCT04472494). As more data
emerge on the fate of Tregs in COVID-19 patients, the aforementioned clinical observations could be
taken as a basis for initiating randomised trials on CTLA-4-Fc (abatacept) therapy in moderate or severe
COVID-19 patients. Though abatacept therapy in autoimmune patients is not associated with a
predisposition to infection, selection of the dosage and the window of treatment are critical to strike a
balance between inflammation and protective immune response to SARS-CoV-2. We believe that early
treatment with abatacept might not benefit COVID-19 patients as it would curtail effective protective
immune responses against SARS-CoV-2. For the initial exploration, the treatment regimen adapted for the
tocilizumab therapy of COVID-19 patients or even the abatacept regimen used in DMARD treatment of
rheumatic diseases could be considered.
Emmanuel Stephen-Victor
1
, Mrinmoy Das
1
, Anupama Karnam
2
, Bruno Pitard
3
, Jean-François Gautier
2,4
and
Jagadeesh Bayry
2
1
Division of Immunology, Boston Childrens Hospital, Harvard Medical School, Boston, MA, USA.
2
Institut National de
la Santé et de la Recherche Médicale; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris,
Paris, France.
3
Université de Nantes, CNRS ERL6001, Inserm 1232, CRCINA, Nantes, France.
4
Service de Diabétologie,
Endocrinologie, Nutrition, Centre Universitaire du Diabète et de ses Complications, Hôpital Lariboisière, Université
Paris-Diderot Paris-7, Paris, France.
Correspondence: Jagadeesh Bayry, Institut National de la Santé et de la Recherche Médicale Unité 1138, Centre de
Recherche des Cordeliers, 15 rue de lEcole de Médicine, Paris, F-75006, France. E-mail: jagadeesh.bayry@crc.jussieu.fr
Received: 5 June 2020 | Accepted after revision: 23 June 2020
Conflict of interest: E. Stephen-Victor has nothing to disclose. M. Das has nothing to disclose. A. Karnam has nothing
to disclose. B. Pitard has nothing to disclose. J-F. Gautier has nothing to disclose. J. Bayry reports grants from Agence
https://doi.org/10.1183/13993003.02182-2020 3
CORRESPONDENCE
Nationale de la Recherche, France (Appel Flash COVID-19-COVIMUNE and ANR-19-CE17-0021(BASIN)), outside the
submitted work.
Support statement: Partly supported by grants from Agence Nationale de la Recherche, France (Appel Flash
COVID-19-COVIMUNE and ANR-19-CE17-0021(BASIN)). Funding information for this article has been deposited
with the Crossref Funder Registry.
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https://doi.org/10.1183/13993003.02182-2020 4
CORRESPONDENCE
... However, the clinical observation showed that severe and critical patients had higher level of soluble IL-2R, which became a biomarker for early identification of severe COVID-19 and for predicting the clinical progression (106)(107)(108). The increased levels of soluble IL-2R could potentially scavenge IL-2, suggesting low-dose IL-2 therapy was not the optimal regimens for COVID-19 treatment (109). It is reported that an anti-human IL-2 (hIL-2) antibody can increase the Treg/ Teff (effector T cells) ratio when bound to hIL-2 (110). ...
... By increasing trans-endocytosis and degradation of two ligands, CTLA-4 reduces co-stimulatory signals for T-cells (45). The recombinant Fc-fused CTLA-4 protein, Abatacept has been reported to interfere with T-cell signaling and activation, and therefore it has been used for several years for the immunotherapy of many autoimmune diseases (109). Recently, a clinical trial which uses Abatacept in the therapy of COVID-19 patients has been completed (ClinicalTrials.gov ...
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Coronavirus disease 2019 (COVID-19) has been raging all around the world since the beginning of 2020, and leads to acute respiratory distress syndrome (ARDS) with strong cytokine storm which contributes to widespread tissue damage and even death in severe patients. Over-activated immune response becomes one of the characteristics of severe COVID-19 patients. Regulatory T cells (Treg) play an essential role in maintaining the immune homeostasis, which restrain excessive inflammation response. So FOXP3 ⁺ Tregs might participate in the suppression of inflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides suppressive function, tissue resident Tregs are also responsible for tissue repair. In this review, we mainly summarize the latest research focusing on the change of FOXP3 ⁺ Tregs in the COVID-19 patients, discuss the relationship between disease severity and number change of Tregs and speculate the potential role of FOXP3 ⁺ Tregs during SARS-CoV-2 infection. Furthermore, we introduce some potential Treg-based therapies to improve patients’ outcomes, which include small molecular drugs, antibody drugs, CAR-Treg and cytokine treatment. We hope to reduce tissue damage of severe COVID-19 patients and offer better prognosis through Treg-based therapy.
... Patients with COVID-19 may suffer from an overactive immune system and lung injury due to a reduction of Treg levels. The high frequency of hyperactivated CD25+ T cells may cause immunothrombosis, another symptom of COVID-19 severe manifestations (Kalfaoglu et al., 2020;Stephen-Victor et al., 2020;McGonagle et al., 2020). Another study found that severe COVID-19 patients had a higher number of Tregs with higher levels of FoxP3 expression than mild, recovered, or healthy controls. ...
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... Importantly, this tissue protective effect is independent of the immune suppressive function of Tregs and their classical regulatory role (12). In addition, Tregs have been addressed in the context of SARS-CoV-2 infection and several studies revealed that in patients with severe COVID-19, marked by potent cytokine storm, Tregs might be beneficial for the lung environment, dampening the pro-inflammatory cues and restoring tissue integrity (88) (Figure 3). On the other hand, excessive immune regulation by Tregs may hamper an effective immune response against SARS-CoV-2 and thereby exacerbate disease severity (89). ...
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... This grants importance to interventions with antiinflammatory properties, which is the case for RT [116][117][118]. It is also important to note that regulatory T lymphocyte (Treg) is associated with controlling inflammatory response and is reduced in severely ill patients [119,120], suggesting its important role in COVID-19 progression. In this regard, a previous study showed that RT can upregulate Treg [121] and that the regular practice of RT increases the levels of interleukin-10, an anti-inflammatory cytokine that is mainly produced by Treg cells [117,118]. ...
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Background: In this pandemia, it is essential for rheumatologist and patients to know the relationship between COVID-19 and inflammatory rheumatic diseases (IRD). We want to assess the role of targeted synthetic or biologic disease modifying antirheumatic drugs (ts/bDMARDs) and other variables in the development of moderate-severe COVID-19 disease in IRD. Methods: An observational longitudinal study was conducted (1stMar to 15thApr 2020). All patients from the rheumatology outpatient clinic from a hospital in Madrid with a medical diagnosis of IRD were included. Main outcome: hospital admission related to COVID-19. Independent variable: ts/bDMARDs. Covariates: sociodemographic, comorbidities, type of IRD diagnosis, glucocorticoids, NSAIDs and conventional synthetic DMARDs (csDMARDs). Incidence rate (IR) of hospital admission related to COVID-19, was expressed per 1,000 patients-month. Cox multivariate regression analysis was run to examine the influence of ts/bDMARDs and other covariates on IR. Results: 3,591 IRD patients were included (5,896 patients-month). Concerning csDMARDs, methotrexate was the most used followed by antimalarials. 802 patients were on ts/bDMARDs, mainly anti-TNF agents, and rituximab. Hospital admissions related to COVID-19 occurred in 54 patients (1.36%) with an IR of 9.15 [95%CI: 7-11.9]. In the multivariate analysis, older, male gender, presence of comorbidities and specific systemic autoimmune conditions (Sjoegren, polychondritis, Raynaud and mixed connective tissue disease) had more risk of hospital admissions regardless other factors. Exposition to ts/bDMARDs did not achieve statistical signification. Use of glucocorticoids, NSAIDs, and csDMARDs dropped from the final model. Conclusion: This study provides additional evidence in IRD patients regarding susceptibility to moderate-severe infection related to COVID-19.
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COVID-19 has rapidly developed into a worldwide pandemic with a significant health and economic burden. There are currently no approved treatments or preventative therapeutic strategies. Hundreds of clinical studies have been registered with the intention of discovering effective treatments. Here, we review currently registered interventional clinical trials for the treatment and prevention of COVID-19 to provide an overall summary and insight into the global response.