Cyclic neutropenia (CN): a clue to the control of granulopoiesis

Abstract

A simple quantitative feedback model of granulopoiesis is presented and discussed within the framework of existing data on granulopoiesis in both normals and patients with cyclic neutropenia (CN). The model assumes that the controlled compartment is the bone marrow pool of mature neutrophils (PMNs), which sends a negative feedback signal to the mitotic pool of early granulocyte precursors (i.e., CFU-C, myeloblasts, etc.) thus controlling the granulocyte production rate. Three parameters are found to play important roles in determining the response of the system to perturbations. These are: TM, the granulocyte maturation time; a, a parameter reflecting the strength of the negative feedback exerted by mature PMNs on the granulocyte production rate; and b, a parameter describing the leakiness of the bone marrow for PMN egress. It is shown that depending on the relative magnitudes of a and b, the system will either respond to perturbations with a damped oscillation (a less than b: the normal state) or with a sustained oscillation (a greater than b: the CN state). In both cases, the oscillation period is found to approximately equal 2TM. Deductions of the values of a, b, and TM from experimental data are consistent with the predictions of the model and show an increased value of a in CN relative to the normal state. This suggests an overly active feedback mechanism as the pathophysiologic basis of CN. In addition, the model can explain how various therapeutic agent correct CN and also provides insight into why other hematologic cell lines and CSA oscillate in CN.