Regulatory T Cells for Treating Patients With COVID-19 and Acute Respiratory Distress Syndrome: Two Case Reports

Gladstone, Douglas E.; Kim, Bo Soo; Mooney, Kathy; Karaba, Andrew H.; D’Alessio, Franco R.

doi:10.7326/l20-0681

Cited by 72 publications

(80 citation statements)

References 5 publications

(2 reference statements)

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“…Of late, two COVID-19 patients with acute respiratory distress syndrome (ARDS) were treated twice or thrice with allogeneic, offthe-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].…”

Section: @Erspublicationsmentioning

confidence: 99%

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

et al. 2020

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, 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-β and 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].

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Section: @Erspublicationsmentioning

confidence: 99%

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

et al. 2020

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“…A viable alternative is the use of allogeneic human leukocyte antigen-matched umbilical cord-derived Tregs (UBC-Treg) which can be widely expanded and used on a larger scale. A recent case study used 1x10 8 administration of UBC-Treg in two patients with COVID-19 who had severe respiratory failure, and both demonstrated significant clinical improvement and reduced inflammatory markers four days after starting treatment (287).…”

Section: Immune Cell-based Therapymentioning

confidence: 99%

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

et al. 2020

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Coronavirus Disease 2019 (COVID-19) has been classified as a global threat, affecting millions of people and killing thousands. It is caused by the SARS-CoV-2 virus, which emerged at the end of 2019 in Wuhan, China, quickly spreading worldwide. COVID-19 is a disease with symptoms that range from fever and breathing difficulty to acute respiratory distress and death, critically affecting older patients and people with previous comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and mainly spreads through the respiratory tract, which it then uses to reach several organs. The immune system of infected patients has been demonstrated to suffer important alterations, such as lymphopenia, exhausted lymphocytes, excessive amounts of inflammatory monocytes and macrophages, especially in the lungs, and cytokine storms, which may contribute to its severity and difficulty of establishing an effective treatment. Even though no specific treatment is currently available, several studies have been investigating potential therapeutic strategies, including the use of previously approved drugs and immunotherapy. In this context, this review addresses the interaction between SARS-CoV-2 and the patient's host immune system during infection, in addition to discussing the main immunopathological mechanisms involved in the development of the disease and potential new therapeutic approaches.

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“…There is limited indirect and direct evidence that T regulatory cells (Tregs) have some therapeutic efficacy in severe COVID-19. Il-2 induced Tregs as well as cord blood derived Tregs appeared to rescue patients that were on ventilators in limited studies (53,68). There are other prospective treatments in the pipeline, but the patterns are similar to those of the above approaches.…”

Section: Socs1/3 Antagonist and Severe Covid-19mentioning

confidence: 93%

SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19

2020

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The suppressor of cytokine signaling (SOCS) family of intracellular checkpoint inhibitors has received little recognition compared to other checkpoint inhibitors. Two members of this family, SOCS1 and SOCS3, are indispensable, since SOCS1 knockout in mice results in neonatal death due to interferon gamma (IFNg) induced inflammatory disease, and SOCS3 knockout leads to embryonic lethality. We have shown that SOCS1 and SOCS3 (SOCS1/3) function as virus induced intrinsic virulence factors for influenza A virus, EMC virus, herpes simplex virus 1 (HSV-1), and vaccinia virus infections. Other viruses such as pathogenic pig enteric coronavirus and coronavirus induced severe acute respiratory syndrome (SARS) spike protein also induce SOCS virus intrinsic virulence factors. SOCS1/3 exert their viral virulence effect via inhibition of type I and type II interferon (IFN) function. Specifically, the SOCS bind to the activation loop of receptor-associated tyrosine kinases JAK2 and TYK2 through the SOCS kinase inhibitory region (KIR), which inhibits STAT transcription factor activation by the kinases. Activated STATs are required for IFN function. We have developed a small peptide antagonist of SOCS1/3 that blocks SOCS1/3 inhibitory activity and prevents virus pathogenesis. The antagonist, pJAK2 (1001-1013), is comprised of the JAK2 activation loop, phosphorylated at tyrosine 1007 with a palmitate for cell penetration. The remarkable thing about SOCS1/3 is that it serves as a broad, simple tool of perhaps most pathogenic viruses to avoid innate host IFN defense. We suggest in this Perspective that SOCS1/3 antagonist is a simple counter measure to SOCS1/3 and should be an effective mechanism as a prophylactic and/or therapeutic against the COVID-19 pandemic that is caused by coronavirus SARS-CoV2.

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Regulatory T Cells for Treating Patients With COVID-19 and Acute Respiratory Distress Syndrome: Two Case Reports

Cited by 72 publications

References 5 publications

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19

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