Elevated IFN-c in the CNS of GFAPcR1D mice during both acute and chronic disease excluded limited IFN-c due to sequestration by the transgenic receptor as a mediator of increased clinical severity and mortality. Indeed, enhanced IFN-c production may reflect an attempt to compensate for the loss of IFN-c dependent astrocyte mediated control of inflammation [33] . Sustained expression of pro-inflammatory cytokines, particularly IL-6 and TNF, thus represents a primary mechanism underlying ongoing tissue destruction in GFAPcR1D mice. IL-6 is known to mediate neurological dysfunction [34] and astrocytes are the predominant source of IL-6 during CNS autoimmune disease. Furthermore, its secretion is down regulated by IFN-c induced SOCS activity [17] . On the other hand, sustained TNF implicated dysregulated activation of microglia or macrophages via increased IFN-c or IL-6, as TNF is predominantly secreted by activated CNS macrophages and microglia during EAE [35, 36] . However, the down regulation of microglia activation, including TNF secretion, following interaction with activated astrocytes [37] questions this notion. While both IL-6 and TNF may thus contribute to sustained pathological changes, the source of TNF remains unclear. Similarly, astrocytes are a potential source of the IFN-c induced chemokine CXCL10 during EAE, one of the chemokines controlling T cell recruitment [38] . However, the increased expression of CXCL10 coupled with the inability of the astrocytes in the GFAPcR1D mice to respond to IFN-c suggests altered microglia activation and secretion of CXCL10 [38] or activation of CXCL10 transcription via an independent signaling pathway mediated by TNF or Type 1 interferons [39, 40] .