Recombinant human interleukin-7 reverses T cell exhaustion ex vivo in critically ill COVID-19 patients.
Critically ill
Exhaustion
Immunostimulation
Interleukin-7
SARS-CoV-2
T lymphocytes
Journal
Annals of intensive care
ISSN: 2110-5820
Titre abrégé: Ann Intensive Care
Pays: Germany
ID NLM: 101562873
Informations de publication
Date de publication:
05 Mar 2022
05 Mar 2022
Historique:
received:
06
09
2021
accepted:
13
01
2022
entrez:
5
3
2022
pubmed:
6
3
2022
medline:
6
3
2022
Statut:
epublish
Résumé
Lymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7. Peripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients. Severe COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far. Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.
Sections du résumé
BACKGROUND
BACKGROUND
Lymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.
RESULTS
RESULTS
Peripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.
CONCLUSIONS
CONCLUSIONS
Severe COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far. Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.
Identifiants
pubmed: 35246776
doi: 10.1186/s13613-022-00982-1
pii: 10.1186/s13613-022-00982-1
pmc: PMC8896969
doi:
Banques de données
ClinicalTrials.gov
['NCT04392401']
Types de publication
Journal Article
Langues
eng
Pagination
21Investigateurs
Remi Pescarmona
(R)
Lorna Garnier
(L)
Christine Lombard
(C)
Magali Perret
(M)
Marine Villard
(M)
Sébastien Viel
(S)
Valérie Cheynet
(V)
Elisabeth Cerrato
(E)
Estelle Peronnet
(E)
Jean-François Llitjos
(JF)
Laetitia Itah
(L)
Inesse Boussaha
(I)
Françoise Poitevin-Later
(F)
Christophe Malcus
(C)
Marine Godignon
(M)
Florent Wallet
(F)
Marie-Charlotte Delignette
(MC)
Frederic Dailler
(F)
Marie Simon
(M)
Auguste Dargent
(A)
Pierre-Jean Bertrand
(PJ)
Neven Stevic
(N)
Marion Provent
(M)
Laurie Bignet
(L)
Valérie Cerro
(V)
Jean-Christophe Richard
(JC)
Laurent Bitker
(L)
Mehdi Mezidi
(M)
Loredana Baboi
(L)
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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