Moving the Boundaries of Granulopoiesis Modelling.

Abstract

The human blood cell production system usually remains extremely robust, in terms of cell number or function, with little signs of decline in old age.To achieve robustness, circulating blood cells rely on a formidable production machinery, the hematopoietic system, located in the bone marrow. All circulating blood cells---red blood cells, white blood cells and platelets---are renewed on a daily basis.The hematopoietic system produces an estimated 1e12 cells per day. This is a significant fraction of the 3.7e13 cells in an adult.Robustness is partly due to the short time scales at which cell populations are able to return to equilibrium, combined with large cell numbers and renewal rates. White blood cells (WBCs), among which neutrophils are most prevalent, are the body's first line, innate immune system.Upon infection, WBCs are mobilized from the bone marrow, to increase their number in circulation and fight off pathogen within hours.The 26 billion circulating neutrophils in human have a mean residence time of only 11h in the blood.After their release from the bone marrow, they quickly disappear in the peripheral tissues and are destroyed in the spleen, liver and bone marrow. In addition to the high renewal rate of circulating blood cells, a large number of mature neutrophils, ten times or more the circulating number, is kept in a bone marrow reserve, ready for entering circulation.This high renewal rate and mobilization capability, however, come at a cost. The blood system is an easy target for chemotherapeutic drugs, whose main way of acting is by killing proliferating cells.White blood cells and end especially neutrophils, with their fast turnover, are particularly vulnerable to chemotherapy.Chemotherapy can induce neutropenia---a state of low absolute neutrophil count (ANC)---in cancer patients, which puts them at risk of infection.Homeostatic regulation of white blood cells is mainly controlled by the cytokine Granulocye-Colony Stimulating Factor (G-CSF).G-CSF promotes survival of white blood cell precursors and their differentiation into mature cells.The identification of this protein in the 1980's, and the subsequent development of human recombinant forms of G-CSF paved the way to the treatment of chemotherapy-induced neutropenia.G-CSF therapy as also been successful at treating congenital and other forms of neutropenia.Today, G-CSF is used as an adjuvant in several anti-cancer treatment protocols.The aim of the adjuvant therapy is to minimize the length of the neutropenic episodes.However, exogenous G-CSF administration interferes with white blood cell production regulation.What should be a straightforward effect--administer G-CSF to cause the ANC to increase--turns to be more complicated than that.For instance, it was observed that early timing of G-CSF administration could lead to prolonged neutropenic phase.Thus, in order to take advantage of the full potential of G-CSF, a detailed understanding of the physiological interaction between neutrophils and exogenous G-CSF is necessary. In this issue of the Bulletin, Craig and colleagues present a physiological modelof neutrophil production that includes a detailed modelling of the kinetics of G-CSF.