Wednesday, 25 March 2015

Animal studies going one way or the other.


Ding X, Yan Y, Li X, Li K, Ciric B, Yang J, Zhang Y, Wu S, Xu H, Chen W, Lovett-Racke AE, Zhang GX, Rostami A. Silencing IFN-γ Binding/Signaling in Astrocytes versus Microglia Leads to Opposite Effects on Central Nervous System Autoimmunity. J Immunol. 2015 pii: 1303321. [Epub ahead of print]

IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, whereas much less is known about its effects on CNS cells, especially in vivo. In this study, we dissected the in vivo effects and mechanisms of IFN-γ binding/signaling in astrocytes and microglia, and found that IFN-γ signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-γ binding/signaling in astrocytes alleviated EAE, whereas in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, whereas blocking IFN-γ binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ binding/signaling in astrocytes alleviated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of multiple sclerosis therapies directed at CNS cells.

Most studies suggest that disease forming cells produce interferon gamma and it activates immune and other cells and so would be predicted to make things worse and it was given to MS and yes it made things worse.

However in animals you give interferon gamma and it stops EAE and you knockout out gamma interferon and it makes EAE worse. Is this why it was given in MS. Not sure, the worsening in MS was published in 1987 the worsening the knockouts was published in 1996 by more than one group and worsening with blockade with antibodies was in 1988 so maybe the mouse stuff came too late and it was because interferon was known to be anti-viral and they tried alpha (no effect), beta (inhibition) and gamma (worsening). In this study they remove interferon signalling from macrophages and EAE gets worse like the global knockout, and remove it from astrocytes and EAE gets better. So it shows things are not simple black and white, but who is going to go near MS with interferon gamma again? 

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