It is now accepted that the CNS and immune system reciprocally regulate each other through discrete cellular and molecular mechanisms. In addition to Multiple Sclerosis (MS), it has become apparent that disregulated CNS-immune interactions play a role in the pathogenesis of various CNS disorders, including Alzheimer's disease and stroke. In Experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, systemic administration of TGF-pi inhibits the onset of EAE, while our lab recently demonstrated that its overproduction solely in the CNS exacerbates EAE. These seemingly opposite results can be reconciled by the idea that TGF-^I within the CNS creates a local environment specifically modulating the T cell population accumulated within the CNS and ultimately affecting the pathogenesis of EAE. Therefore my hypothesis is that TGF-3 expressed in the CNS facilitates the survival, proliferation and accumulation of T cells, which propagate immune-mediated CNS disease. I will address my hypothesis in two aims: 1) determine how CNS TGF-pi affects T cell accumulation and characterize this population of cells and 2) determine whether increased production of TGF-pi in the CNS is sufficient to induce spontaneous EAE in mice harboring MOG TCR transgenic mice. If indeed TGF-PI within the local environment of the CNS modulates the accumulation, survival and proliferation of the T cell population accumulated within the CNS, this could have important implications for our understanding of immune-mediated CNS diseases such as MS and quite possibly also virus induced CNS diseases. Our findings would shift attention from a predominant focus on peripheral T cell immunology to a more CNS centric view and a consideration of the local environment or niche. Furthermore, the results of my studies may provide support for using ALK5 inhibitors, such as IN1130 which prevents signal transduction of TGF-fl, as potential therapeutic intervention for immune-mediated CNS disease.
| Ding, Zhaoqing; Mathur, Vidhu; Ho, Peggy P et al. (2014) Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. J Exp Med 211:189-98 |
| Villeda, Saul A; Luo, Jian; Mosher, Kira I et al. (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90-4 |
