Systemic cytokine immunotherapy for experimental cytomegalovirus retinitis in mice with retrovirus-induced immunodeficiency.
OBJECTIVE
To evaluate and compare the in vivo administration of interleukin-2 (IL-2) or interleukin-12 (IL-12) in the immunotherapy of necrotizing retinitis caused by murine cytomegalovirus (MCMV) in mice with a retrovirus-induced immunodeficiency syndrome (MAIDS).


METHODS
Adult C57BL/6 mice with MAIDS of 8 weeks' duration were treated with either a single intramuscular injection of polyethylene glycol-modified human recombinant IL-2 (PEG-IL-2) or multiple intramuscular injections of murine recombinant IL-12; untreated mice with MAIDS received phosphate-buffered saline. Two days later, the left eyes of all mice were inoculated with MCMV by subretinal injection and evaluated at day 6 for intraocular MCMV titers or at day 10 for frequency of necrotizing MCMV retinitis.


RESULTS
Infectious MCMV was significantly reduced in whole eyes of PEG-IL-2-treated mice with MAIDS (2.8 log10), but not in whole eyes of IL-12-treated animals (4.4 log10) when compared with whole eyes of untreated animals with MAIDS (4.5 log10). Similarly, whereas eyes from approximately 80% of IL-12-treated and untreated mice with MAIDS showed histopathologic features consistent with classic necrotizing MCMV retinitis (full-thickness retinal necrosis associated with virus inclusions and cytomegalocytes), none (0%) of PEG-IL-2-treated animals with MAIDS showed classic MCMV retinitis. Instead, eyes from these animals showed either retinal folding or outer retinal atrophy, a pattern of histopathology similar to that observed in eyes from immunologically normal C57BL/6 mice inoculated subretinally with MCMV.


CONCLUSIONS
These results provide proof-of-principle for the hypothesis that systemic cytokine immunotherapy will reduce the frequency of CMV retinitis in a setting of retrovirus-induced immunosuppression. Because of the striking differential effects of IL-2 and IL-12 on MCMV-retinitis in mice with MAIDS, the authors conclude that cytokine immunotherapy for cytomegalovirus-induced retinitis is cytokine-specific, even for such cytokines as IL-2 and IL-12 that have T cell regulation in common.
Dix
R D
RD
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida, USA.
Giedlin
M
M
Cousins
S W
SW
D000818:Animals; D004195:Disease Models, Animal; D015828:Eye Infections, Viral / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D005260:Female; D006566:Herpesviridae Infections / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D007167:Immunotherapy; D018664:Interleukin-12 / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D007378:Interleukins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016183:Murine Acquired Immunodeficiency Syndrome / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D018146:Muromegalovirus / Q000302:isolation & purification*; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000627:therapeutic use; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000821:virology; D012173:Retinitis / Q000473:pathology / Q000628:therapy* / Q000821:virology
D007376:Interleukin-2; D007378:Interleukins; D011994:Recombinant Proteins; D018664:Interleukin-12; D011092:Polyethylene Glycols