Abstract
Purpose::
We have shown previously that down-regulation of the perforin cytotoxic pathway occurs in mice with retrovirus-induced immunodeficiency syndrome (MAIDS) that are susceptible to murine cytomegalovirus (MCMV) retinitis. Additional studies have shown that spleen cells and MCMV-infected eyes from mice with MAIDS harbor significantly elevated levels of interleukin-4 (IL-4), a Th2 cytokine thought to inhibit preferentially the perforin cytotoxic pathway. We therefore performed a pilot study to test the hypothesis that suppression of IL-4 during MAIDS will increase resistance to MCMV retinitis.
Methods::
Groups of C57BL/6 mice with MAIDS were injected systemically with either 15 ug of anti-mouse IL-4 antibody or normal mouse antibody on days -3, 0, +3, and +6 relative to subretinal MCMV injection. Normal healthy mice not receiving antibody injections served as an additional control. Following subretinal MCMV injection, MCMV-infected eyes from all animal groups were collected at 10 days postinfection and scored for frequency of MCMV retinitis. IL-4 protein levels (pg/ml) were also determined by ELISA for spleen cells recovered from all animal groups.
Results::
As expected, 87% (7/8) of mice with MAIDS treated with normal mouse antibody developed MCMV retinitis, whereas 0% of normal healthy mice developed retinal disease. In comparison, 37% (3/8) of mice with MAIDS treated with IL-4 antibody developed MCMV retinitis. Antibody-induced suppression of IL-4 in these animals was confirmed by ELISA that showed ~2.1 pg/ml of IL-4 protein in their spleen cells versus ~8.6 pg/ml of IL-4 in spleen cells from untreated MAIDS mice versus ~0.6 pg/ml of IL-4 in spleen cells from normal healthy mice.
Conclusions::
This pilot study provides proof-of-principal that suppression of IL-4 during MAIDS will increase resistance to experimental MCMV retinitis. These findings support our working hypothesis that IL-4 synthesis by Th2 CD4+ T cells during retrovirus-induced immunodeficiency preferentially dampens the perforin cytotoxic pathway that subsequently allows susceptibility to MCMV retinitis during MAIDS.
Keywords: retinitis • cytomegalovirus • AIDS/HIV