Watch out for your kidneys…the new remyelinating option

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Circulating transforming growth factor-β1 facilitates remyelination in the adult central nervous system. Hamaguchi M, Muramatsu R, Fujimura H, Mochizuki H, Kataoka H, Yamashita T. Elife. 2019 May 9;8. pii: e41869. doi: 10.7554/eLife.41869

We are all searching for new treatment options and so many mice are getting all sorts of drug in the hope that we can find one. In this study they identify transforming growth factor beta1 as a remyelination agents. Now you can all read this paper as it is open access so follow the link if interested. I don’t normally do these EAE and cuprizone papers as they are “Cure of the Week”, but as this is published in Elife claimed to contain Nature quality stuff, I thought it would be useful.

You can even see the referees comments.

So as this will link to the altmetric I think I will give it a blog.

Now Elife says that the animals studies should report to be consistent with the ARRIVE guidelines but they don’t really practice what is being preached and I think point 19 of those says put your results in the context of the human condition. This recieved no mention, so I say in case you read this and think it is a good idea to inject people with active TGF beta in the hope that it cause remyelination…..Stop. If you want to save your kidneys

TGF beta is what we call a pleiotrophic cytokine, so it goes many things, like making fibroblasts grow, inhibitng immune functction and here it makes oligodendrocytes remyelinate. It has no effect on acute EAE, but about 25-30 years ago it inhibited immunity and blocked EAE and if you inhibited EAE they got worse and didn’t recover…so pretty clear and reproducible that TGFb can be immunosuppressive and was consistently reported. So what is the difference here the referees concerns were not really addressed.

Johns LD, Flanders KC, Ranges GE, Sriram S Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1. J Immunol. 1991;147(6):1792-6

Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Kuruvilla AP, Shah R, Hochwald GM, Liggitt HD, Palladino MA, Thorbecke GJ. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2918-21.

CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta. Karpus WJ, Swanborg RH.J Immunol. 1991 Feb 15;146(4):1163-8.

Transforming growth factors beta 1 and beta 2: cytokines with identical immunosuppressive effects and a potential role in the regulation of autoimmune T cell function. Schluesener HJ, Lider O.J Neuroimmunol. 1989 ;24(3):249-58.

etc, etc.

OK they started at the peak of disease but in past there is still time to influence recovery. But it is claimed “This study resolves a long-standing debate about the therapeutic mechanism by which systemic TGF-β1 acts in the treatment of EAE “. I think there will be a few people protesting here and some groups spent some time promoting the concept of Th3, which were immunosuppressive T cells that produced transforming growth factor. These papers are wiped away by this without any real mention. In my opinion it is really unlikely that the effects seen in all those EAE papers were related to demyelination/remyelination. Indeed studies were done in rats in models, where there is essentially no demyelination so it can’t really explain all the effects.

Anyway with all those EAE experiments in mind, they ploughed on to a clinical trial. Now transforming growth factor is a cytokine that is produced as an inactive molecule with a cap over the active site. So it only gets activated once the cap comes off, because you don’t want active TGF beta every where. But the neuros did not think of this and used the active TGF (in this case TGF-B2) and it went every where and probably caused the kidneys to be fibrosed (Scarred) because it make fibroblasts grow.

July 01, 1998; 51 (1) Phase 1 trial of transforming growth factor beta 2 in chronic progressive MS. P. A. Calabresi, N. S. Fields, H. W. Maloni, A. Hanham, J. Carlino, J. Moore, M. C. Levin, S. Dhib-Jalbut, L. R. Tranquill, H. Austin, H. F. McFarland, M. K. Racke Neurology DOI: https://doi.org/10.1212/WNL.51.1.289. Luckily this the kidney problems were reversible, but sends a warning not considered about the translatability.

Indeed this may be a central problem for many remyelination candidates as they are never specific for oligodendrocytes and so anything that promotes repair may cause side effects.

In this study they depleted TGF-B with a reduction in platelets, so is this why people with MS did badly when they go ITP (Autoimmune disease reducing platelets) after alemtuzumab treatment? This is why you have to have your bloods tested every month for 4 years after the last dose.

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