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 both treated and untreated joints (the "contralateral effect"). We used a mouse delayed-type hypersensitivity (DTH) model to investigate this phenomenon. Adenoviral delivery of the vIL-10 gene suppressed DTH reactions in injected and contralateral paws. T lymphocytes recovered from immunized mice injected 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 antigen 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 mouse IL-10 also suppressed DTH reactions by adoptive transfer when pulsed with the inciting antigen. Collectively, these data suggest a mechanism for the contralateral effect in which genetically modified macrophages and DCs present antigen in the context of high, local concentrations of vIL-10, thereby generating unresponsive T lymphocytes. These findings suggest new ways in which to treat immune-driven diseases by gene and cell therapy.
Whalen
J D
JD
Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15312, USA.
Thomson
A W
AW
Lu
L
L
Robbins
P D
PD
Evans
C H
CH
D000256:Adenoviridae / Q000502:physiology*; D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015551:Autoimmunity; D003713:Dendritic Cells / Q000276:immunology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000627:therapeutic use; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016753:Interleukin-10 / Q000235:genetics*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology
D016753:Interleukin-10