Clinical trial NCT01735565: Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant
Official title: Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Bone Marrow Transplant
Keywords: NET formation
neutraphil extracellular traps
post-engraftment immune system
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2012-11-28
Enrollment: 23
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients who are undergoing bone marrow transplant, as well as patients who have completed a bone marrow transplant within the previous year at Huntsman Cancer Institute and Primary Children's Medical Center will be identified as possible participants.

Brief summary: This is a prospective observational study to determine the point after bone marrow transplant in adults and children at which the neutrophils derived from the transplanted stem cells are competent to form functional neutrophil extracellular traps (NETs). Furthermore, given the importance of platelet function for NET formation, we also plan to examine platelet activation and function as well as the platelet transcriptome using the same clinical samples.

Detailed description: Background and Introduction

The role of the human polymorphonuclear leukocytes (PMNs) in the acute inflammatory response is well documented. PMNs play a fundamental role in the innate immune response and are rapidly recruited to areas of injury or inflammation where they participate in bacterial phagocytosis and killing. Disorders associated with a deficiency or impairment of PMN function (neutropenia, chronic granulomatous disease (CGD), leukocyte adhesion deficiency) predispose to infections with bacteria and fungi. Regulation of this potent component of the acute inflammatory response is imperative to prevent overwhelming infections often associated with morbidity and mortality.

Recently, neutrophils isolated from healthy adult donors were shown to undergo programmed cell death distinct from apoptosis and necrosis to form neutrophil extracellular traps (NETs). NETs are extensive lattices of extracellular DNA and chromatin decorated with anti-microbial proteins and degradative enzymes such as myeloperoxidase and neutrophil elastase (NE). NETs effect extracellular killing of bacteria and fungi. The laboratory of Christian Yost, MD recently characterized impaired NET formation as a novel innate immune deficiency of human newborn infants and showed that PMNs isolated from the cord blood of newborn infants, both term and preterm, demonstrated impaired NET formation and extracellular bacterial killing as compared to PMNs isolated from healthy adults. However, the timing for developmental maturation of newborn infant PMN NET formation remains unknown.

Stem cells for bone marrow transplants originate from cord blood, peripheral stem cells, or bone marrow stem cells. Regardless of the source of these stem cells, patients receiving a bone marrow transplant are essentially building a new immune system, as if they were a newborn baby. Immune system reconstitution is a continuous process whose components can take up to 1 to 2 years to fully recover. Severe infections in bone marrow transplant patients occur and may be associated with deficient PMN NET formation by way of impaired extracellular bacterial containment and killing. We hypothesize that the increased risk of infection attributed to bone marrow transplant recipients results, in part, from deficient PMN NET formation by the nascent, post-engraftment immune system which is molecularly and functionally similar to that of a newborn baby. We plan to determine the point after transplant at which the neutrophils derived from the transplanted stem cells are competent to form functional NETs. Furthermore, given the importance of platelet function for NET formation, we also plan to examine platelet activation and function as well as the platelet transcriptome using the same clinical samples.

Eligibility criteria: Inclusion Criteria:

* Within one year of bone marrow transplant
* Informed consent

Exclusion Criteria:

* No specific exclusion criteria

Primary outcomes:
measure: Post-engraftment maturation of NET formation
timeFrame: 1 year
Secondary outcomes:
measure: Post-engraftment platelet function
timeFrame: 1 year
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Utah
name: Christian Yost, MD
role: PRINCIPAL_INVESTIGATOR
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