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J. Z. Kuo, M. Zandian, K. Mott, D. Gate, T. Town, H. Ghiasi; Leukocyte Involvement in CNS Demyelination After Ocular Infection With Recombinant HSV-1 Expressing IL-2. Invest. Ophthalmol. Vis. Sci. 2010;51(13):825.
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To identify: (1) the cellular infiltrates that are involved in CNS demyelination in mice ocularly infected with a recombinant HSV-1 expressing IL-2, and (2) the role(s) of leukocyte populations in HSV-1-induced demyelination.
We ocularly infected female BALB/c and C57BL/6 mice with HSV-IL-2 or control viruses (HSV-IL-4, HSV-IFN-γ, HSV-1 McKrae, or KOS) and probed for leukocyte involvement in HSV-IL-2-induced demyelination. Specifically, we determined the role(s) of T cell subsets and CD25 in CNS demyelination in knockout mice. We elucidated the contribution of TH1 and TH2 responses to demyelination in infected STAT4- and STAT6-deficient mice, and examined the roles of both induced and natural T cell sub-populations to CNS demyelination in HSV-IL-2 and KOS infected recipient SCID mice. Finally, we determined the effects of bone marrow-derived macrophages and TH1-promoting IL-12p70 DNA immunization in blocking demyelination in HSV-IL-2 infected mice.
Histological examination of mice infected with HSV-IL-2 demonstrated that natural killer cells, dendritic cells, B cells, or CD25 (IL-2rα) do not play any role in HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer studies suggested that CD8+ T cells are the primary inducers of CNS demyelination, while CD4+ T cells play a certain, but sub-dominant role. Transfer of uninfected or infected BM-derived macrophages to recipient WT mice did not block CNS demyelination in HSV-IL-2 infected mice. However, HSV-IL-2-induced demyelination was blocked by injection of infected mice with IL-12p70 DNA, but not IL-23, IL-27, or IL-35 DNA.
This study demonstrates that suppression of the IL-12p70 by IL-2 both in vitro and in vivo causes T cells to become auto-aggressive. Interruption of this important immunoregulatory axis results in demyelination of the optic nerve, the brain, and the spinal cord in HSV-IL-2-infected mice.
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