In order to study in vivo the enhanced granulopoiesis that occurs during acute inflammation, 1-3 sterile metallic copper rods were inserted subcutaneously into mice either at the same place (one abscess) or at different sites (multiple abscesses). Diffusion chambers filled with bone marrow cells were implanted intraperitoneally for 3 days. When a single abscess was created, the granulocytic content of the diffusion chamber increased similarly whatever the number of inserted copper rods. However, there was a direct relationship between the number of abscesses and the number of granulocytic cells harvested from the diffusion chambers. In order to investigate the role of T-lymphocytes in the production of diffusible stimulating factors that act on diffusion chamber granulopoiesis, cyclosporin A (CyA) was given to the mice with implanted copper rods. CyA abrogated the induced enhancement of CFU-S, CFU-GM and mature granulocyte numbers inside the diffusion chamber. The stimulatory effect of inflammation on diffusion chamber granulopoiesis was not observed in T-lymphocyte-deficient nude mice. These data suggest that in vivo stimulation of granulopoiesis is related to the level of inflammation, and that this effect requires the functional integrity of T-lymphocytes.
It was demonstrated previously that mice undergoing an inflammatory reaction induced by subcutaneous (SC) implantation of copper rods, produce humoral factors that initially enhance, but subsequently inhibit, diffusion chamber (DC) granulopoiesis. This provided evidence that granulopoiesis is under the control of both humoral stimulators and inhibitors. In order to test the granulopoietic regulatory mechanism in leukaemic mice, we investigated the regulatory role of granulopoietic humoral inhibitors during in vivo granulopoiesis. We noticed that mice suffering from acute myeloid leukaemia (AML) are unable to augment the production of these humoral inhibitory factors when acute inflammation is induced, since no change in DC cell content was observed with or without prior inflammation. Moreover, unlike healthy mice, the serum of leukaemic mice withdrawn during the inhibition phase of acute inflammation did not show any inhibitory activity toward granulocyte—monocyte (GM) colony growth in vitro. Our results also show that increased levels of normal humoral inhibitors do not influence the proliferation and/or differentiation of leukaemic cells implanted in diffusion chamber cultures.
In previous studies, we have shown that mice undergoing an inflammatory reaction induced by subcutaneous (s.c.) implantation of copper rods elaborate humoral factors that initially enhance, and subsequently inhibit, diffusion chamber (DC) granulopoiesis. In order to quantify the inhibition of DC granulopoiesis after inflammation, one to three copper rods were implanted s.c. either at the same place (1 abscess), or at different sites (multiple abscesses). There was an inverse relationship between the increase in the number of abscesses, and the number of DC granulocytic cells measured in the inhibitory phase. To investigate the role of T lymphocytes in the release of putative inhibitory factor(s) that act on DC cells, cyclosporin A (CyA), a T lymphocyte function inhibitor, was given orally each day (0.75 mg) to mice, starting two days before copper implantation. CyA abrogated the inflammation-related inhibition on DC spleen colony-forming units (CFU-s), granulocyte-macrophage colony-forming units (CFU-gm), and total cell production. To confirm these results, DC were implanted in T cell deficient nude mice where no inhibition of DC cells was observed after inflammation. In conclusion, our data suggest that the in vivo inhibition of granulopoiesis is related to the level of the inflammatory stimulus and requires the functional integrity of T cells.
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