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-stimulati ng factor (GM-CSF) is a prominent candidate gene for this approach because this cytokine can prime immune responses to 'self' tumour or other weak ant igens. Prior studies suggested that GM-CSF induces accumulation and differe ntiation 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, lo cal changes were characterized by the accumulation of myeloid cells, a subs equent infiltration of lymphocytes and then myonecrosis. Intraperitoneal in jection also induced an accumulation of myeloid cells, an increase in CD3-p ositive 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) al ong with high levels of surface MHC class II, a characteristic morphology, and endocytosis of FITC-dextran suggested in vivo differentiation of dendri tic cells after i.p. injection of Ad-mGM-CSF. Systemic effects were observe d after i.m. and i.p. injection of Ad-mGM-CSF. All mice developed hepatospl enomegaly resulting from extramedullary haematopoiesis. These changes were specific to GM-CSF as they were not seen in mice injected with an adenoviru s vector without a transgene. Our observations indicate that adenoviral tra nsfer of GM-CSF is a powerful tool for inducing local and systemic expansio n of haematopoietic cells. The local expansion of myeloid cells displaying signs of dendritic cell differentiation, as characterized for the peritonea l cell compartment, can explain the potency of GM-CSF when used as an adjuv ant in genetic immunotherapy.