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Effects of excess granulocyte-macrophage colony stimulating factor (GM-CSF) in mice infected with a GM-CSF retrovirus
1Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Abstract:
To study the effects of dysregulated granulocyte-macrophage colony stimulating factor (GM-CSF) production, a retroviral vector (MPZen) containing a GM-CSF cDNA has been used to infect murine bone marrow cells prior to their transplantation into lethally-irradiated recipients. Animals transplanted with 1 x 10(6) bone marrow cells 14 to 21 days after transplantation displayed shortness of breath, trembling to the touch, and dragging of the hind limbs. These animals were shown to have increased peripheral blood neutrophil counts (x 200), decreased marrow cellularity (but with increased neutrophil and macrophage frequency) and increased spleen cellularity (with up to a 40-fold increase in neutrophil, macrophage and eosinophil frequency). Examination of sections of tissues from infected mice showed massive infiltration of neutrophils and macrophages in muscle, lungs, liver, and variable infiltration of these cells in lymphoid tissues and the eye. Haemopoietic tissues produced high levels of GM-CSF (10(5) Units/10(6) cells) and the serum contained up to 5.5 x 10(5) Units of GM-CSF per ml.
Insights
Dysregulated granulocyte-macrophage colony-stimulating factor (GM-CSF) production causes severe inflammation and tissue infiltration by immune cells in mice. This leads to significant health issues, including respiratory distress and hind limb dysfunction.
Area of Science:
- Hematology
- Immunology
- Molecular Biology
Background:
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) is crucial for immune cell development.
- Dysregulation of GM-CSF can lead to inflammatory conditions.
Purpose of the Study:
- To investigate the in vivo effects of sustained, high-level GM-CSF production.
- To model the consequences of GM-CSF dysregulation in a murine transplantation system.
Main Methods:
- Murine bone marrow cells were infected with a retroviral vector encoding GM-CSF cDNA.
- Infected cells were transplanted into lethally-irradiated recipients.
- Hematological parameters, tissue infiltration, and GM-CSF levels were analyzed.
Main Results:
- Transplanted mice exhibited shortness of breath, trembling, and hind limb dysfunction.
- Significant increases in peripheral blood neutrophils and spleen cellularity were observed.
- Massive infiltration of neutrophils and macrophages was found in multiple organs, including lungs, liver, and muscle.
Conclusions:
- Sustained high-level GM-CSF production induces severe systemic inflammation and multi-organ myeloid cell infiltration.
- GM-CSF dysregulation is a key factor in the pathogenesis of inflammatory diseases.
- This model provides insights into GM-CSF-driven pathology.