Friday, 6 December 2013

Towards Immunosuppression without side-effects?

McNally JP, Elfers EE, Terrell CE, Grunblatt E, Hildeman DA, Jordan MB, Katz JD. Eliminating Encephalitogenic T Cells without Undermining Protective Immunity. J Immunol. 2013  [Epub ahead of print]

The current clinical approach for treating autoimmune diseases is to broadly blunt immune responses as a means of preventing autoimmune pathology. Among the major side effects of this strategy are depressed beneficial immunity and increased rates of infections and tumors. Using the experimental autoimmune encephalomyelitis model for human multiple sclerosis, we report a novel alternative approach for purging autoreactive T cells that spares beneficial immunity. The moderate and temporally limited use of etoposide, a topoisomerase inhibitor, to eliminate encephalitogenic T cells significantly reduces the onset and severity of experimental autoimmune encephalomyelitis, dampens cytokine production and overall pathology, while dramatically limiting the off-target effects on naive and memory adaptive immunity. Etoposide-treated mice show no or significantly ameliorated pathology with reduced antigenic spread, yet have normal T cell and T-dependent B cell responses to de novo antigenic challenges as well as unimpaired memory T cell responses to viral rechallenge. Thus, etoposide therapy can selectively ablate effector T cells and limit pathology in an animal model of autoimmunity while sparing protective immune responses. This strategy could lead to novel approaches for the treatment of autoimmune diseases with both enhanced efficacy and decreased treatment-associated morbidities.
We rarely talk about animal studies because it is science fiction. But we keep our eyes open.

I like the concept of selectively targeting the disease forming cells because this is the way to control the immune response without increasing risk of infections and cancers. The risk is if you get it wrong and it stimulates rather than inhibits then your MS gets worse. This has happened, so it is a real risk. This is perhaps the most compelling data to me that can support the autoimmune hypothesis. 

So when I saw the title I thought yes and sat done for a right riveting read....Sadly I should stop now and call on the Trade Description Act.

This study shows that if you take a cytostatic drug Etoposide an anti-cancer drug that kills dividing/ activating cells you can inhibit the development of EAE and you can give it in a way that may not stop responses to infection. 

So if you have a drug that you know kills activated cells and you know when they are activated you can get them to work in EAE in a few doses.......Hey Presto. We showed you can do this with one injection with another topoisomerase inhibitor and x and y and z and a and b and c and d etc and has been shown by others with drug e, f, g, h, i etc etc. 


However Etopiside will also kill cells that fight of infection if given at a certain time, so if you have an infection at the same time as autoimmunity the infection would become a problem. 

However, a problem with MS is you don't know when disease is going to strike and for every clinical relapse there may be 10 or more MRI relapses in the form of lesions. So do you have to deliver agent all the time? If you do then will you have problems. 

This could be rapidly tested with Mitoxantrone but is this going to happen? 

We do not usually give DMT at the time of relapse, which is what is happening in animals in many studies including this one.
Will Neuros change their habits? 
The use of cytostatic drugs that kill activated dividing cells has been tried in MS and we know the answer(s).

Actually I think the principle of short courses of immune modulators is not a bad idea. Do you have to give these drugs forever? 
In animals you don't!

If you are a company you want people to buy as much drug as possible e.g injecting Glaterimer acetate every day. Now you may not need to have to do it that often with a 3 times a week,etc. Alemtuzumab is an induction therapy only needed for a few days a year. Will ocreluzimab be an induction therapy or will they try flog it as monthly dose?

If you are not on drug do you feel safe?

There have been comments this week asking which DMT should one take in addition to an induction therapy.So does it feel better to take something daily even if it is not needed?

Timing is important give Cyclophosphamide another anti-cancer, drug, sometimes used in MS, which kills dividing cells (including hair and gut cells) before sensitization and it can kill regulating cells and make disease worse experimentally. Give it after sensitization and kill dividing effector cells and it makes disease better. One well timed dose can wipe out EAE to something much more impressive than found here with Etoposide. 

Is the idea Novel?

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