Dysfunctional Myelopoiesis and Myeloid-Derived Suppressor Cells in Sepsis
NCT ID: NCT05110937
Last Updated: 2025-12-26
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
450 participants
OBSERVATIONAL
2022-01-04
2027-04-30
Brief Summary
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Detailed Description
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This Program will investigate in human surgical sepsis the underlying mechanisms that drive 'dysfunctional myelopoiesis', expansion of MDSC populations, suppressed T-cell quantities/function, and the development of patient's immunosuppressive/inflammatory endotypes. We will primarily focus on how MDSC expansion evolves over time in an observational study that follows surgical sepsis patients who do or do not rapidly recover. There are three specific aims: Aim 1. To test the hypothesis that perpetuation of host MDSCs after acute surgical sepsis drives poor long-term clinical outcomes in surgical sepsis, including but not limited to increased secondary infections. Aim 2. To test the hypothesis that failure to recover from surgical sepsis is driven by modifiable epigenetic alterations in circulating MDSCs that induce and prolong immunosuppressive endotypes. Aim 3. To identify the distinct immunosuppressive mechanisms of MDSCs from surgical sepsis patients over time, including immunometabolism, check-point inhibition, reactive oxygen and nitrogen production, and substrate availability. Using the established clinical infrastructure of the Sepsis and Critical Illness Research Center (SCIRC), a team science approach will be employed with collaborating PI's coming from multiple clinical and basic science disciplines. Aim 4. To test the hypothesis that in response to an initial inflammatory stimulus (severe blunt trauma) associated with a high risk of in-hospital sepsis, bone marrow (BM) hematopoietic stem cells (HSCs) promote immunosuppressive myelopoiesis at the expense of lymphopoiesis. With subsequent sepsis development, MDSCs induce their continued expansion through exocrine and paracrine signaling to HSCs. HSCs and MDSCs derived from severe blunt trauma patients will be analyzed for epigenetic and functional changes that initiate sepsis and continue the expansion of immunosuppressive MDSCs.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Sepsis
Blood collection: Blood will be collected from patient at day 4, day 7, day 14-21 and at 3 and 6 months.
Blood sampling
Blood sampling
Healthy Controls
Blood Collection.
The healthy volunteer participants will donate a blood sample. These controls will allow the investigators to determine if the values obtained are accurate, reliable, and repeatable.
Blood sampling
Blood sampling
Trauma
Blood collection: Blood will be collected from patient at day 4, day 7, day 14-21 and at 3 and 6 months.
Blood sampling
Blood sampling
Interventions
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Blood sampling
Blood sampling
Eligibility Criteria
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Inclusion Criteria
2. meets criteria for sepsis/septic shock by Sepsis-3 consensus criteria.
1. All adults age ≥ 18 years
2. Blunt trauma patient with a. Injury Severity Score (ISS) greater than or equal to 25 b. ISS \> 15 and one of the following: i. \> 4 units of PRBC or \>3 units of whole blood or \>1500 ml of autogenous blood product in the first 24 hours of admission ii. AIS (acute injury score) \> 2 spine iii. Shock on arrival (Systolic blood pressure (SBP) \< 90)
OR
c. ISS \> 15 and two of the following: i. Age \> 55 ii. AIS \> 2 chest iii. +ETOH (ethyl alcohol) on arrival iv. Any red blood cell transfusion in first 24 hours
Exclusion Criteria
2. have comorbidity burden or goals of care that preclude recovery after sepsis. These criteria include:
a. irreversible shock (death \<12 hours) b. uncontrollable surgical source of sepsis c. patients deemed to be futile care or have advanced directives limiting resuscitative efforts d. alternative diagnoses causing shock state (e.g., hemorrhage, myocardial infarction or pulmonary embolus) e. known HIV infection with CD4+ count \<200 cells/mm3 g. severe traumatic brain injury with unencumbered assessment of GCS equaling 3 on admission to the intensive care unit.
3. known pregnancy
4. enrollment \>96 hours after suspected sepsis onset
5. pre-hospitalization bedridden performance status (WHO/Zubrod score ≥4)
6. subsequent clinical adjudication diagnosis not consistent with sepsis/septic shock by Sepsis-3 criteria.
7. Burn injury greater than 20% total body surface area (tBSA)
Trauma Participant:
1. Patients not expected to survive greater than 48 hours.
2. Prisoners.
3. Pregnancy.
4. Previous bone marrow transplantation.
5. Patients with End Stage Renal Disease.
6. Patients with any pre-existing hematological disease.
7. Patients deemed to be futile care or have advanced directives limiting resuscitative efforts.
8. Known HIV infection with CD4+ count \<200 cells/mm3
9. Burn injury greater than 20% tBSA
18 Years
100 Years
ALL
Yes
Sponsors
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National Institute of General Medical Sciences (NIGMS)
NIH
University of Florida
OTHER
Responsible Party
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Principal Investigators
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Lyle Moldawer, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Florida
Philip Efron, MD
Role: PRINCIPAL_INVESTIGATOR
University of Florida
Tyler Loftus, MD
Role: PRINCIPAL_INVESTIGATOR
University of Florida
Locations
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UF Health at Shands hospital
Gainesville, Florida, United States
Countries
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Central Contacts
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Facility Contacts
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Jennifer Lanz, MSN
Role: primary
Ruth Davis, BSN
Role: backup
Other Identifiers
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