Viral IL-10 gene transfer inhibits DTH responses to soluble antigens: Evidence for involvement of genetically modified dendritic cells and macrophages

Expression of the viral interleukin-10 (vIL-10) gene within one joint of an animal with polyarticular, inflammatory arthritis suppresses disease in bo th treated and untreated joints (the "contralateral effect"). We used a mou se delayed-type hypersensitivity (DTH) model to investigate this phenomenon . Adenoviral delivery of the vIL-10 gene suppressed DTH reactions in inject ed and contralateral paws. T lymphocytes recovered from immunized mice inje cted with the adenoviral vector (ad-vIL-10) were unable to transfer the DTH response, but were not inhibitory. Peritoneal exudate cells recovered from mice injected intraperitoneally with ad-vIL-10 inhibited DTH reactions in recipient mice, but only when the donor mice had been sensitized to the ant igen used to incite the DTH response. Dendritic cells (DCs) recovered from the draining lymph nodes of mice injected with ad-vIL-10 behaved similarly. Bone-marrow-derived DCs cultured ex vivo with ad-vIL-10 or recombinant mou se IL-10 also suppressed DTH reactions by adoptive transfer when pulsed wit h the inciting antigen. Collectively, these data suggest a mechanism for th e contralateral effect in which genetically modified macrophages and DCs pr esent antigen in the context of high, local concentrations of vIL-10, there by generating unresponsive T lymphocytes. These findings suggest new ways i n which to treat immune-driven diseases by gene and cell therapy.