The Potential of Mesenchymal Stromal Stem Cells to Correct Immune and Metabolic Dysfunctions in Circulating Immune Cells During Sepsis: An Ex Vivo Pilot Study.

The Potential of Mesenchymal Stromal Stem Cells to Correct Immune and Metabolic Dysfunctions in Circulating Immune Cells During Sepsis: An Ex Vivo Pilot Study.

Sepsis is a life-threatening organ dysfunction caused by the host's dysregulated immune response to infection. It represents a major global public health challenge. A state of post-septic compensatory immunosuppression may contribute to excess mortality by promoting secondary infections, thereby prolonging the stay in the intensive care unit and increasing the risk of death.

New therapeutic strategies to complement antimicrobial treatments-which may correct sepsis-induced functional alterations in immune cells (such as endotoxin tolerance and reduced HLA-DR expression), partly mediated by metabolic abnormalities-are currently being investigated. Among these, mesenchymal stromal cells (MSCs) appear particularly promising. They are capable of reprogramming immune cells by redirecting certain metabolic pathways, notably improving mitochondrial function. MSCs generally have an anti-inflammatory effect in preclinical models of infection, particularly in the early phase of severe ventilated pneumonia, as illustrated by the animal model we have developed, and preliminary trials are currently underway in humans. The ability of CSMs to correct sepsis-induced immunosuppression has not yet been explored. Nevertheless, CSMs possess the ability to communicate with the inflammatory microenvironment in which they are found, conferring plasticity to their response.

We hypothesize that CSMs could correct certain immune and metabolic dysfunctions in circulating immune cells from patients with sepsis meeting severity criteria who are admitted to the intensive care unit.

Furthermore, priming (or prior stimulation) of CSMs could enable a more precise and personalized therapeutic approach, with the possibility of directing CSMs toward a pro-inflammatory (CSM1) or anti-inflammatory (CSM2) phenotype through prior incubation with specific agonists (LPS; IFN-γ/TNF, respectively) before their administration. Depending on the patient's immune status (pro-inflammatory or anti-inflammatory phase), such a personalized approach would optimize treatment with CSMs.

Inclusion Criteria:

• Patient or authorized representative, informed and having given consent

• Age ≥ 18 years

• Patients admitted for sepsis defined by the association as:

  • Clinically or microbiologically documented infection

  • SOFA-2 score ≥ 2

    • Or +2 points if pre-existing organ dysfunction

• Complicated

  • ARDS (Berlin criteria (1))

    • Acute respiratory failure
    • AND Bilateral pulmonary opacities (X-ray or CT scan) with no evidence of predominant hydrostatic edema
    • AND PaO₂/FiO₂ ≤ 300 mmHg under invasive or non-invasive ventilation with PEEP ≥ 5 cmH₂O

  • or septic shock (2)

    • Vasopressors required to maintain mean arterial pressure (MAP) ≥ 65 mmHg
    • AND arterial lactate > 2 mmol/L
    • AND despite adequate fluid resuscitation

• Blood sample may be collected within 72 hours of admission to the intensive care unit

Exclusion Criteria:

• Individuals not enrolled in or not eligible for a social security program

• Individuals subject to a legal protection order

• Pregnant women, women in labor, or breastfeeding women

• Known severe immunodeficiency prior to sepsis:

  • cytostatic chemotherapy within the previous 3 months,
  • previously known neutropenia < 500/mm³ (within the past month) not attributed to sepsis,
  • active hematologic malignancy currently undergoing treatment,
  • allogeneic bone marrow transplant < 1 year ago,
  • solid organ transplant receiving immunosuppressants
  • corticosteroid therapy ≥ 0.5 mg/kg/day of prednisone equivalent for > 3 weeks,
  • anti-TNF or anti-IL-6 biologic therapy within the past 3 months,
  • HIV infection with a detectable viral load while not on treatment

Secondary exclusion criteria :

- A diagnosis of sepsis was ruled out following a comprehensive medical evaluation and/or an alternative diagnosis was identified that explains the elevated SOFA-2 score