A novel virotherapy encoding human interleukin 7 enhances ex vivo lymphocyte functions in immunosuppressed septic shock and critically ill COVID-19 patients
Critical Care
; 26(SUPPL 1), 2022.
Article
in English
| EMBASE | ID: covidwho-1793896
ABSTRACT
Introduction:
After viral or bacterial sepsis, most intensive care unit (ICU) patients enter a state of profound immunosuppression contributing to patients' worsening. Transgene has developed an immunotherapy based on a viral vector encoding human interleukin-7 (hIL-7) to restore both innate and adaptive immune responses. Here, we assessed the capacity of hIL-7 to improve ex vivo T lymphocyte function from septic shock and COVID-19 patients.Methods:
Primary human hepatocytes were transduced with MVAhIL- 7-Fc, a recombinant Modified Vaccinia virus Ankara (MVA) encoding the hIL-7 fused to the human IgG2 Fc fragment, or with empty MVA as control. Cell culture supernatants were harvested for further assays. T cells were collected from ICU patients (septic shock = 11, COVID- 19 = 29) and healthy donors (n = 21). STAT5 phosphorylation, cytokine production (ELISpot and intracellular staining) and cell proliferation were assessed upon TCR stimulation with supernatants containing or not hIL-7 produced after MVA transduction or with the counterpart recombinant hIL-7 (rhIL-7).Results:
Patients with viral and bacterial sepsis display T lymphocyte alterations compared to healthy donors with a decreased production of cytokines and a decreased proliferation capacity. Supernatant containing hIL-7 induces STAT5 phosphorylation in CD3 lymphocytes of all patients. With 90% of responders, hIL-7 boosts cytokines production (single and double IFN-TNF) and T lymphocytes proliferation capacity at the same level as rhIL-7 in both cohorts whereas empty MVA has no effect.Conclusions:
This study indicates that hIL-7-Fc produced after MVA transduction initiates IL-7 signaling through the phosphorylation of STAT5 and restores ex vivo human lymphocyte functions in cells from septic patients with acquired immunosuppression. This proof-of-concept study, along with experimental results in animal models, supports the clinical development of the MVA-hIL-7-Fc in sepsis immunosuppressed patients.
CD3 antigen; endogenous compound; immunoglobulin Fc fragment; immunoglobulin G2; interleukin 7; STAT5 protein; T lymphocyte receptor; tumor necrosis factor; adult; animal cell; animal experiment; animal model; animal tissue; cell culture; cell proliferation; conference abstract; controlled study; coronavirus disease 2019; cytokine production; enzyme linked immunospot assay; ex vivo study; female; human; immunosuppressive treatment; intensive care unit; liver cell; lymphocyte; lymphocyte proliferation; male; nonhuman; proof of concept; protein phosphorylation; sepsis; septic shock; signal transduction; supernatant; T lymphocyte; Vaccinia virus Ankara; viremia; virotherapy
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Critical Care
Year:
2022
Document Type:
Article
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