Local and systemic effects after adenoviral transfer of the murine granulocyte-macrophage colony-stimulating factor gene into mice.
Vectors encoding immunostimulatory genes are under investigation for their use as adjuvants for immunotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a prominent candidate gene for this approach because this cytokine can prime immune responses to 'self' tumour or other weak antigens. Prior studies suggested that GM-CSF induces accumulation and differentiation of antigen-presenting cells, particularly dendritic cells that can initiate immunity. To evaluate this model in vivo, we performed i.m. and i.p. injections of an adenovirus vector encoding murine GM-CSF (Ad-mGM-CSF) and evaluated local and systemic effects. After intramuscular injection, local changes were characterized by the accumulation of myeloid cells, a subsequent infiltration of lymphocytes and then myonecrosis. Intraperitoneal injection also induced an accumulation of myeloid cells, an increase in CD3-positive T and a decrease in B220-positive B lymphocytes. Expression of the dendritic cell marker CD11c on 48 +/- 9% of the peritoneal cells (n = 6) along with high levels of surface MHC class II, a characteristic morphology, and endocytosis of FITC-dextran suggested in vivo differentiation of dendritic cells after i.p. injection of Ad-mGM-CSF. Systemic effects were observed after i.m. and i.p. injection of Ad-mGM-CSF. All mice developed hepatosplenomegaly resulting from extramedullary haematopoiesis. These changes were specific to GM-CSF as they were not seen in mice injected with an adenovirus vector without a transgene. Our observations indicate that adenoviral transfer of GM-CSF is a powerful tool for inducing local and systemic expansion of haematopoietic cells. The local expansion of myeloid cells displaying signs of dendritic cell differentiation, as characterized for the peritoneal cell compartment, can explain the potency of GM-CSF when used as an adjuvant in genetic immunotherapy.
Burger
J A
JA
Department of Medicine, Division of Hematology/Oncology, University of California San Diego, School of Medicine, La Jolla, CA 92093-0663, USA.j1burger@ucsd.edu
Baird
S M
SM
Powell
H C
HC
Sharma
S
S
Eling
D J
DJ
Kipps
T J
TJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000648:ultrastructure; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006367:HeLa Cells; D006411:Hematopoiesis, Extramedullary; D006801:Humans; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007962:Leukocytes / Q000276:immunology; D008099:Liver / Q000033:anatomy & histology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000033:anatomy & histology; D009929:Organ Size; D013154:Spleen / Q000033:anatomy & histology / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000648:ultrastructure
D016178:Granulocyte-Macrophage Colony-Stimulating Factor