[Adenovirus long-term expression of thrombopoietin in vivo: a new model for myeloproliferative syndrome and osteomyelofibrosis].
Using a new adenoviral vector (Ad) construct, we expressed human thrombopoietin (TPO) cDNA (AdTPO) in mice with various inherited immune deficiency syndromes such as nude, SCID and NOD-SCID mice. Immune normal Balb/c mice and a vector construct without TPOcDNA (AdNull), respectively, were used for controls. All animals (3 per group) were treated with a single application of 10(9) PFU (plaque forming unit) of Ad (AdTPO or AdNull) intraperitoneally on day 0. Four to 5 weeks following AdTPO administration, SCID and NOD-SCID mice demonstrated peak concentration of PLT of 12- to 14-fold normal value simultaneously with maximum concentration of PMNs (10- to 12-fold normal value). Later on these animals had a chronic thrombocytosis. In contrast, Balb/c mice and nude mice experienced PLT peak concentration of 4- to 6-fold normal value without granulocytosis 1 to 2 weeks following AdTPO treatment. Only nude mice had chronically elevated PLTs. In contrast, Balb/c mice developed thrombocytopenia due to cross-reacting anti-TPO antibodies. Animals with chronic thrombocytosis revealed increased content of CFU-G/GM, CFU-GEMM and CFU-Meg in bone marrow compared with controls. In contrast, Balb/c mice showed decreased content of CFUs if anti-TPO-antibodies were present. Histologically, only SCID mice developed severe osteomyelofibrosis and osteomyelosclerosis, hepato-splenomegaly, extramedullary hematopoiesis in liver and lung and ultimately suffered of progressive pancytopenia, anisocytosis, fragmentocytosis and a lethal wasting syndrome. In contrast, NOD-SCID mice which demonstrated similar extent of TPO overexpression and in addition to the B- and T-cellular immune deficiency harbour defective monocytes and macrophages, did not develop fibrotic changes of the bone marrow. From these results, we conclude (1) chronic TPO overexpression in vivo may lead to thrombocytosis and granulocytosis with expansion of CFU-GM, -GEMM and -Meg; (2) in vivo expression of adenovirally mediated TPOcDNA depends on immune competency of the host; (3) functionally normal monocytes and macrophages are indispensable for development of secondary osteomyelofibrosis and (4) adenovirally mediated expression of xenogeneic transgenes may brake immune tolerance for the respective self protein leading to autoimmune phenomena. Our in vivo model might provide further insights into the pathophysiology of secondary osteomyelofibrosis and may prove useful in designing new strategies for immune therapies of cancer.
Frey
B M
BM
Memorial Sloan-Kettering Cancer Center, New York, USA.
Rafii
S
S
Crystal
R G
RG
Moore
M A
MA
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D017921:Mastadenovirus / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009196:Myeloproliferative Disorders / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000235:genetics*; D013154:Spleen / Q000473:pathology; D013926:Thrombopoietin / Q000235:genetics*
D013926:Thrombopoietin
Adenovirale Langzeit-Expression von Thrombopoietin in vivo: ein neues Modell für myeloproliferatives Syndrom und Osteomyelofibrose.