Natalizumab is a humanized monoclonal antibody against the leukocyte adhesion molecule very late antigen (VLA)-4, and is currently an approved therapy for patients with relapsing-remitting multiple sclerosis (RRMS). However, it is unknown whether natalizumab is beneficial for progressive forms of MS. Therefore, we assessed the effects of anti-VLA-4 monoclonal antibody (mAb) therapy in a progressive experimental autoimmune encephalomyelitis (EAE) mouse model. Notably, we found that early therapy could significantly reduce the severity of progressive EAE, while treatment initiated at an advanced stage was less efficient. Furthermore, we observed the accumulation of a novel subset of GM-CSF-producing CD11b+CD4+ T cells in the CNS throughout disease progression. Importantly, early therapeutic anti-VLA-4 mAb treatment suppressed the accumulation of these GM-CSF-producing CD11b+CD4+ T cells in the CNS along with activated microglia/macrophages populations, and also conferred a protective effect against inflammation-mediated neurodegeneration, including demyelination and axonal loss. Collectively, our data suggest that early treatment with anti-VLA-4 mAb can provide neuroprotection against progressive CNS autoimmune disease by preventing the accumulation of pathogenic GM-CSF-producing CD11b+CD4+ T cells in the CNS.
For many years we thought of EAE as being autoimmune and EAE was focussed on studying autoimmunity. But now that in-roads are being made in RRMS and progressive MS is the major unmet need.
So a real progressive MS model is something that would be exceptionally useful.
But is it progressive EAE?…it looks absolutely no different from the standard chronic EAE in mice that has been used to study autoimmunity targeted at relapsing MS. Progressive MS does not respond well to peripheral immunosuppressive drugs, yet in this paradigm immunosuppression reigns supreme.
Does this model develop progressive disease…yes probably but it after disease has become established.
Why do animal studies when human studies are so advanced and the drug is being already tested in humans for this purpose?…..It may show a mechanism that helps getting the drug through the regulators and also it is something that helps the marketing as it keeps the compound in the public eye, whilst the trials are ongoing.
It is interesting the study was funded by Biogen makers of Tysabri, who are testing their drug for its ability to stop progressive MS. For licensing I have heard that the FDA like a bit of mechanistic animal data. So this all sounds perfect. (Although Biogen had no input in the experimental plan!). One don’t need to meddle with the design it’s tried and tested..so keep on marketing:-)