Thursday, 22 May 2014

Glaterimer acetate doesn't do everything

Bittner S, Ruck T, Göbel K, Henschel C, Afzali AM, Göb E, Müntefering T, Kleinschnitz C, Wiendl H, Meuth SG. Effects of Glatiramer Acetate in a Spontaneous Model of Autoimmune Neuroinflammation. Am J Pathol. 2014 May 9. pii: S0002-9440(14)00218-1. doi: 10.1016/j.ajpath.2014.03.009. [Epub ahead of print]

Glatiramer acetate (GA) (Copaxone), a well-established drug for the treatment of multiple sclerosis, is believed to modulate numerous pathways including antigen-presenting cells or cytokine responses. A new generation of spontaneous experimental autoimmune encephalomyelitis mouse models has been developed that mimic certain aspects of multiple sclerosis spectrum disorders. 

We assessed the effects of GA in the opticospinal encephalomyelitis model, which involves MOG35-55 peptide-specific T cells and B cells. A nonsignificant trend toward lower disease incidence was found for GA treatment (started on postnatal day 20). Immunohistochemical evaluations revealed no significant differences for inflammatory lesions and demyelination, cytokine production, proliferation, and cell surface markers of immune cells between GA-treated and PBS-treated (control) mice. Although a good correlation was found between the disease score of individual mice and some readout parameters (eg, immunohistochemical staining), this was not the case for others (eg, IFN-γ production). It seems plausible that a major effect of GA lies on alternative immunological pathways, such as initiating of an immune response that is not sufficiently reflected in this spontaneous experimental autoimmune encephalomyelitis model. Thus, the main advantage of the opticospinal encephalomyelitis model in our hands lies in elucidation of factors influencing the onset of experimental autoimmune encephalomyelitis (eg, susceptibility factors). The models seem less suitable for investigation of disease severity modifications after therapeutic interventions.


A cross of a transgenic mouse where all its T cells react to MOG and all its B cells/Antibodies react to MOG and it is then prone to disaster and the spontaneous development of EAE, without the need of adjuvants that induce the immune response. Here the damage accumulates n the optic nerve and the spinal cord rather than the brain, just like most EAE models. The severity of disease correlated with the degree of immune infiltration. This has elegantly been found shown in other studies. http://multiple-sclerosis-research.blogspot.co.uk/2013/10/imaging-of-whole-tissues.htm. In this study they then used glaterimer acetate and it didn't work i.e. non-significant trend = it didn't work or maybe the experiment wasn't powered enough. So with this failure, it was felt that it may be more useful to study the triggers of disease rather than using it as a treatment tool. Maybe this invalidates the model because it does not reflect the clinical situation. 

Whilst it may indeed be difficult to stop disease in these animals, before throwing it away, it is interesting that if you look at the published studies of GA activity in EAE, the studies showing potent activity occurs when GA is mixed with the immunizing antigen i.e. myelin in the immunizing adjuvant during sensitization. This step is missing in this current study......

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