Supplying neutrophils from the bone marrow to the tissues

Comment on Cheretakis et al, page 2821

Absolute neutrophil counts (ANCs) or differential counts of white blood cells reliably reflect the body's neutrophil supply under normal steady-state conditions. However, when neutrophil production is perturbed by drugs, infections, chemotherapy, or hematopoietic transplantation, the ANC becomes less reliable as a proxy for the neutrophil supply.

In this issue of Blood, Cheretakis and colleagues present a novel study on the recovery of blood and tissue neutrophils after bone marrow transplantation in mice. The study shows that after transplantation, the capacity for a tissue neutrophil response in the lungs and peritoneum precedes the recovery of neutrophils in the blood. Long ago, clinicians learned that patients often become afebrile and can make pus before the blood neutrophil count recovers. This study helps us to understand this important response just a bit better.

About 50 years ago, just at the beginning of modern cancer chemotherapy and hematopoietic transplantation, Athens et al¹  at the University of Utah and Cronkite and Fliedner²  at the Brookhaven laboratories in New York laid the foundations for our understanding of the formation and fate of neutrophils. They used radioisotopes, principally tritiated thymidine and phosphorous-32-labeled diisopropyl fluorophosphate, to label blood cells for their now classic studies. These studies established the short blood half-life and rapid turnover of blood neutrophils and the requirement of a very high production rate of neutrophils by the bone marrow to maintain normal levels of neutrophils in the blood.

The trafficking of neutrophils from the blood to the tissue has always been more difficult to study. Rebuck and Crowley³  introduced the “skin window technique” in the 1940s, a simple technique used to measure effects of many diseases and drugs on in vivo neutrophil migration. The oral rinse technique (ie, washing the mouth with saline to recover the neutrophils that have exuded around the teeth) is another simple method to study the tissue neutrophil response.⁴  The present study was prompted by intriguing findings in a study of neutrophil recovery after chemotherapy in children, using the oral rinse technique.⁵ 

Cheretakis et al used enhanced green fluorescent protein (E-GFP) to label the transplanted marrow in syngeneic mice and trace mature neutrophils from the marrow through the blood to tissue sites of inflammation. In control animals, transplant recipients, and transplant recipients treated with granulocyte colony-stimulating factor (G-CSF), the E-GFP-labeled neutrophils could be counted in the blood, measured in peritoneal exudates, and counted in bronchoalveolar lavage fluid after Pseudomonas aeruginosa infection of the lungs. As detailed in the report, blood neutrophil counts do not fully reflect the capacity to deliver neutrophil to the tissues. Consistently, neutrophil recovery anteceded blood recovery, and the protection from infection parallels the tissue neutrophil response, as reflected by the clearance of the inoculated organisms. G-CSF treatment appeared to enhance the recovery of the tissue response, and the use of E-GFP was a novel approach to studying this important phenomenon. ▪