Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant

Completed

• Conditions: Bone Marrow Transplant

• Registration Number: NCT01735565
• Lead Sponsor: University of Utah

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2012-06
• Study First Submitted: 2012-11-22
• Study First Submitted QC: 2012-11-22
• Study First Posted: 2012-11-28
• Primary Completion: 2014-03
• Status Verified: 2016-07
• Study Completion: 2016-07
• Last Update Submitted: 2016-08-09
• Last Update Posted: 2016-08-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

• Within one year of bone marrow transplant
• Informed consent

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Exclusion Criteria

• No specific exclusion criteria

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Post-engraftment maturation of NET formation	1 year	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.

Secondary Outcome Measures

Name	Time	Method
Post-engraftment platelet function	1 year	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.

Trial Locations

Locations (3)

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Huntsman Cancer Institute; 🇺🇸 Salt Lake City, Utah, United States

Primary Children's Medical Center; 🇺🇸 Salt Lake City, Utah, United States