Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant
Bone Marrow Transplant
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant|
- Post-engraftment maturation of NET formation [ Time Frame: 1 year ] [ Designated as safety issue: No ]The time to post-engraftment maturation of NET formation capability in PMNs isolated from pediatric and adult patients undergoing bone marrow transplantation will be measured by serial blood sampling/analysis over the course of a year after transplant.
- Post-engraftment platelet function [ Time Frame: 1 year ] [ Designated as safety issue: No ]Post-engraftment platelet function, transcriptome, and their potential influence on NET formation by PMNs will be measured by serial blood sampling/analysis over the course of a year after transplant.
Biospecimen Retention: Samples With DNA
|Study Start Date:||June 2012|
|Study Completion Date:||July 2016|
|Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Post bone marrow transplant
Patients who are undergoing bone marrow transplant, as well as patients who have completed a bone marrow transplant within the previous year.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01735565
|United States, Utah|
|Huntsman Cancer Institute|
|Salt Lake City, Utah, United States, 84112|
|Primary Children's Medical Center|
|Salt Lake City, Utah, United States, 84113|
|University of Utah|
|Salt Lake City, Utah, United States, 84132|
|Principal Investigator:||Christian Yost, MD||University of Utah|