MICE LACKING BOTH GRANULOCYTE-COLONY-STIMULATING FACTOR (CSF) AND GRANULOCYTE-MACROPHAGE CSF HAVE IMPAIRED REPRODUCTIVE CAPACITY, PERTURBEDNEONATAL GRANULOPOIESIS, LUNG-DISEASE, AMYLOIDOSIS, AND REDUCED LONG-TERM SURVIVAL

Mice lacking granulocyte colony-stimulating factor (G-CSF) are neutrop enic with reduced hematopoietic progenitors in the bone marrow and spl een, whereas those lacking granulocyte-macrophage colony-stimulating f actor (GM-CSF) have impaired pulmonary homeostasis and increased splen ic hematopoietic progenitors, but unimpaired steady-state hematopoiesi s. These contrasting phenotypes establish unique roles for these facto rs in vivo, but do not exclude the existence of additional redundant f unctions. To investigate this issue, we generated animals lacking both G-CSF and GM-CSF. In the process of characterizing the phenotype of t hese animals, we further analyzed G-CSF- and GM-CSF-deficient mice, ex panding the recognized spectrum of defects in both. G-CSF-deficient an imals have a marked predisposition to spontaneous infections, a reduce d long-term survival, and a high incidence of reactive type AA amyloid osis, GM-CSF-deficient mice have a modest impairment of reproductive c apacity, a propensity to develop lung and soft-tissue infections, and a similarly reduced survival as in G-CSF-deficient animals. The phenot ype of mice lacking both G-CSF and GM-CSF was additive to the features of the constituent genotypes, with three novel additional features: a greater degree of neutropenia among newborn mice than in those lackin g G-CSF alone, an increased neonatal mortality rate, and a dominant in fluence of the lack of G-CSF on splenic hematopoiesis resulting in sig nificantly reduced numbers of splenic progenitors. In contrast to newb orn animals, adult mice lacking both G-CSF and GM-CSF exhibited simila r neutrophil levels as G-CSF-deficient animals. These findings demonst rate that the additional lack of GM-CSF in G-CSF-deficient animals fur ther impairs steady-state granulopoiesis in vivo selectively during th e early postnatal period, expand the recognized roles of both G-CSF an d GM-CSF in vivo, and emphasize the utility of studying multiply defic ient mouse strains in the investigation of functional redundancy. (C) 1997 by The American Society of Hematology.