Trial Information

Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant

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.