| Abstract: |
Thrombopoietin (TPO) cDNA can be effectively delivered in vivo by adenovectors. Immune normal mice (BALB/c) and syngeneic mice with variable degrees of immune dysfunction nu, SCID, and NOD-SCID) were treated with an adenovirus vector expressing the human TPO cDNA (AdTPO). Platelet peaks were significantly higher in SCID and NOD-SCID mice compared with BALB/c and nu mice. Human plasma TPO concentration correlated with the platelet counts. SCID and NOD-SCID mice exhibited also granulocytosis and increased numbers of hemopoietic progenitors in bone marrow. Following platelet peak, BALB/c mice developed autoantibodies against murine TPO leading to thrombocytopenia and depletion of megakaryocytes and hemopoietic progenitors in bone marrow. AdTPO-treated SCID mice developed osteomyelofibrosis and extramedullary/extrasplenal hemopoiesis. In contrast, NOD-SCID mice with a similar magnitude of TPO overexpression did not show fibrotic changes in bone marrow. We conclude, first, that a chronic high level of TPO overexpression stimulates megakaryocytopoiesis and myelopoiesis leading to thrombocytosis and granulocytosis. Second, increased megakaryocytopoiesis is not sufficient for development of secondary osteomyelofibrosis. The functionally deficient monocytes and macrophages of NOD-SCID mice probably prevented fibrotic marrow changes. Third, immune deficiency enhances expression of adenovirally mediated transgenes, and fourth, xenogeneic transgene delivered by adenovector to a host with normal immune functions may induce loss of immune tolerance and autoimmune phenomenon. |
| Keywords: |
myelofibrosis; human cell; nonhuman; pathophysiology; protein blood level; animal cell; mouse; animals; mice; bone marrow cells; animal model; mice, scid; strain difference; mice, inbred balb c; genetic vectors; gene expression regulation; immunological tolerance; mice, nude; immunocompromised host; mice, inbred nod; clone cells; combined immunodeficiency; complementary dna; erythrocytes; platelet count; dna, complementary; virus expression; virus vector; blood platelets; thrombopoietin; injections, intraperitoneal; granulocytes; adenoviruses, human; megakaryopoiesis; humans; human; male; female; priority journal; article
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