Myeloid-Derived Suppressor Cells in Sepsis
Study Details
Study Description
Brief Summary
Adverse outcomes in surgical sepsis patients are secondary to dysregulated emergency myelopoiesis, and expansion of myeloid-derived suppressor cells. Here we propose to determine the underlying mechanisms behind the increased expansion of these leukocyte populations and the underlying mechanisms that drive inflammation and immune suppression.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
Our overarching hypothesis is that the consequences of surgical sepsis (death and poor quality of life) are the result of an unresolving host leukocyte dyscrasia, similar to other chronic conditions such as cancer and autoimmune disease. Specifically, the preferential expansion and self-perpetuation of myeloid-derived suppressor cells (MDSCs), propagated in part through epigenetic changes in both bone marrow (BM) progenitors and MDSCs, drives non-acute infectious and noninfectious complications after sepsis.
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Sepsis Blood collection: Blood will be collected from patient at day 4, day 7, day 14-21 and at 3 and 6 months. |
Other: Blood sampling
Blood sampling
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| 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. |
Other: Blood sampling
Blood sampling
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Outcome Measures
Primary Outcome Measures
- The total number of neutrophils and early myeloid derived suppressor cells will be measured and will be used to determine the magnitude of myelopoiesis dysfunction. [6 months]
The total number of neutrophils and early Myeloid derived suppressor cells will be measured at sepsis onset and during hospitalization and at 3 and 6 months.
Eligibility Criteria
Criteria
Inclusion Criteria:
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age ≥18 years
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placement on the electronic medical record (EMR) EPIC™ based sepsis managements standard operating procedures (SOPs)
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meets criteria for sepsis/septic shock by Sepsis-3 consensus criteria.
Exclusion Criteria:
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have had a prior episode of sepsis during this hospitalization.
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have disease states that predispose to significant immune system dysfunction
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have comorbidity burden or goals of care that preclude recovery after sepsis. These criteria include:
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irreversible shock (death <12 hours)
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uncontrollable surgical source of sepsis
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patients deemed to be futile care or have advanced directives limiting resuscitative efforts
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alternative diagnoses causing shock state (e.g., hemorrhage, myocardial infarction or pulmonary embolus)
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severe congestive heart failure (NY Heart Association Class IV)
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known HIV infection with CD4+ count <200 cells/mm3
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chronic liver disease with MELD score ≥15
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severe traumatic brain injury (evidence of neurologic injury on CT scan and GCS<8)
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known pregnancy
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enrollment >96 hours after suspected sepsis onset
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pre-hospitalization bedridden performance status (WHO/Zubrod score ≥4)
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pre-existing state of CCI (ICU length of stay ≥14 days with SOFA>5)
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interfacility transfer patients with >96 hours critical illness prior to transfer
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subsequent clinical adjudication diagnosis not consistent with sepsis/septic shock by Sepsis-3 criteria.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UF Health at Shands hospital | Gainesville | Florida | United States | 32610 |
Sponsors and Collaborators
- University of Florida
- National Institute of General Medical Sciences (NIGMS)
Investigators
- Principal Investigator: Lyle Moldawer, PhD, University of Florida
- Principal Investigator: Philip Efron, MD, University of Florida
- Principal Investigator: Tyler Loftus, MD, University of Florida
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB202100559
- RM1GM139690
- R35GM140806