Chronic Expression of Murine flt3 Ligand in Mice Results in Increased Circulating White Blood Cell Levels and Abnormal Cellular Infiltrates Associated With Splenic Fibrosis

Abstract

The effect of chronic expression of flt3 ligand (FL) on in vivowith progressive fibrosis and infiltration by abnormal lymphoreticular cells. Abnormal cell infiltration also occurred in hematopoiesis was studied. Retroviral vector-mediated gene transfer was used in a mouse model of bone marrow other organ systems, including bone marrow and liver. In situ immunocytochemistry on liver sections showed that the transplantation to enforce expression of mouse FL cDNA in hematopoietic tissues. As early as 2 weeks posttransplanta-cellular infiltrate was CD3 " /NLDC145 " /CD11c " , but B220 Ï and F4/80 Ï , suggestive of a mixed infiltrate of dendritic cells tion, peripheral blood white blood cell counts in FL-overexpressing recipients were significantly elevated compared and activated T lymphocytes. Infiltration of splenic blood vessel perivascular spaces resulted in vascular compression with controls. With the exception of eosinophils, all nucleated cell lineages studied were similarly affected in these and eventual occlusion, leading to splenic necrosis consistent with infarction. These results show that FL can affect animals. Experimental animals also exhibited severe anemia and progressive loss of marrow-derived erythropoiesis. All both myeloid and lymphoid cell lineages in vivo and further demonstrate the potential toxicity of in vivo treatment with of the FL-overexpressing animals, but none of the controls, died between 10 and 13 weeks posttransplantation. Upon FL. ᭧ 1997 by The American Society of Hematology. histological examination, severe splenomegaly was noted, 76

Chronic overexpression of membrane‐bound flt3 ligand by T lymphocytes in severe aplastic anaemia

“…As overexpression of FL leads to tissue fibrosis in a mouse model (Juan et al , 1997), we were interested whether long‐term exposure to high endogenous FL, in both its soluble and membrane‐bound forms, causes fibrosis of tissues accessible for examination in patients with chronic severe AA. Tissue from splenectomized patients and BM biopsies from patients with treatment‐refractory disease were examined histologically for the presence of fibrotic degeneration (Fig 6).…”

“…Potential clinical applications of FL include haemopoietic stem cell transplantation and cancer immunotherapy based on in vivo properties of FL such as mobilization of haemopoietic stem cells to the circulation, radioprotection and anti‐tumour effects (Lynch et al , 1997; Papayannopoulou et al , 1997; Gratwohl et al , 1998). However, a potential risk of in vivo administration of FL has recently been raised by reports on the occurrence of severe splenic fibrosis and leukaemic predisposition in mice transplanted with retrovirally transduced BM cells expressing high levels of FL (Juan et al , 1997; Hawley et al , 1998). Chronically elevated FL in AA offers a chance to test these questions in humans.…”

“…Levels of membrane‐bound FL were also determined in classical autoimmune diseases and in graft‐versus‐host disease (GVHD). As necrosis and fibrosis of the spleen and other organs were described in mice overexpressing FL (Juan et al , 1997), we examined splenectomy specimens and BM biopsies of patients with treatment‐refractory AA for evidence of degenerative changes resulting in fibre increase. Chronic overexpression of membrane‐bound FL was found only in AA, reflecting a long‐lasting defect in haemopoiesis and arguing for the significance of T‐cell‐derived membrane‐bound FL in the pathophysiology of BM failure.…”

In Vitro Culture During Retroviral Transduction Improves Thymic Repopulation and Output After Total Body Irradiation and Autologous Peripheral Blood Progenitor Cell Transplantation in Rhesus Macaques

“…SCF has also been shown to promote survival without resulting in proliferation or differentiation [33]. Flt3 ligand has little effect in vitro on early progenitors, whereas in vivo administration leads to major alterations of different hematopoietic organs [34, 35]. MDGF is a specific growth factor for the platelet lineage [36].…”

The Molecular Control of Hematopoiesis: Progress and Problems with Gene Manipulation

“…This approach, involving cDNAs for GM‐CSF [1], G‐CSF [2], interleukin 3 (IL‐3) [3], leukemia inhibitory factor (LIF) [4], Epo [5], IL‐6 [6], flt3 ligand (FL) [7] and TPO [8], produced animals with extreme elevations of the respective factors and induced an extensive hyperplasia of those hematopoietic subsets known from in vitro studies to be responsive to the particular growth factor. With the reservation that the cellular source of the factor in these mice was not duplicating that in the normal body, the results certainly verified information on lineage‐specific actions of the regulators and predicted accurately enough the likely adverse responses to the injection of excessive doses of these regulators.…”