Cogle et al. Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet. 2004 May 1;363(9419):1432-7.
Is this important for MS? May be it is! The reason I say this is that bone marrow derived stem cells and monocytes use the same receptor as lymphocytes to cross the blood-brain-barrier, i.e. VLA4. Interestingly and importantly, this is the receptor that is blocked by natalizumab. Natalizumab will therefore block the migration of bone-marrow derived stem cells into the brain and spinal cord.
Question: Do MSers on long-term natalizumab treatment, i.e. greater than 10 years or more, develop premature ageing of the brain due to the loss of trophic support from bone-marrow-derived stem cells?
To answer this question we need long-term monitoring of natalizumab-treated MSers to look for markers of premature ageing, i.e. the premature development of age-related neurodegenerative disorders, for example Alzheimer’s, Parkinson’s or other age-related neurodegenerative diseases. This adverse event would take decades to emerge; therefore we need to remain vigilant for unexpected biological consequences of reducing trafficking of stem and other cells into the brain and spinal cord.
Why is this a grand challenge? Simply because so many MSers are now on natalizumab and the first MSers treated are getting to the time window when these potential effects would start emerging. And it is something that keeps me awake at night!
Clues to support my anxieties come from the conjoined mice or parabiosis experiments we have posted on before on this blog:
These experiments show that the ageing brain in older mice responded to something from the circulation of younger mice; the factor seemed to be chemical signals that promote cellular migration across the blood brain barrier. It would be interesting to see what would happen in the conjoined twin or parabiosis experiment if the mice were treated simultaneously with mouse natalizumab; i.e. would mouse natalizumab block the brain regenerative effects of youth in the older mice?
If you are on natalizumab and develop new or unexplained symptoms, that you think may or may not be related to MS, let your MS team know.
Could fingolimod do something similar – for example could it confine stem cells in the bone marrow?And slightly nrelated: you stay the stem cells go into the brain and differentiate into micrglia and neurons. Then why is all the stem cell research working on the immune system? Why do we hear nothing of stem cells making new CNS cells?
I am not aware of fingolimod targeting the migration of bone marrow derived stem cells. Stem cells are released from the bone marrow continously and obviously have a role to play in tissue homeostasis within many organs, including the brain. It appears that the turnover of microglia occurs, i.e. as they die they are replaced by new one. Peripheral stem cell therapies at the moment are using one-off treatment paradigms, this may not be sufficient. The data on whether or not new neurones form is weak and relates to a select group of cells in an ara of the brain called the hippocampus, which is involved in new memory formation. Blocking the latter may have clinical consequences. Neurogenesis, new nerve cells, does appear to be a widespread phenomenon. Therefore it is unlikely that peripheral stem cells will have a major impact in widespread neurodegeneration. The evidence at present points to stem cells having an immunomodulatory effect, i.e. modifying the immune function. They could also influence the environment within the damaged brain making it more likely to allow recovery.
In my experience from 20 years (if memory serves correct!) ago anti-VLA4 (in rat cell culture) didn't have a great effect on blocking lymphocyte migration per se, wheras in these experiments anti-LFA1 was more effective. What it did do was aggregate the lymphocytes into large clumps which would under haemodynamic flow conditions would be flushed through capillaries and thus unable to migrate.
There is a difference; natalizumab is on a IgG4 backbone therefore it scrambles with natural IgG4 antibodies within the body. When it does this it become becomes a bispecific antibody and therefore unable to cross-link cells by targeting VLA4 with both arms of the antibody. So I suspect this is why we don't see clumping of cells in the human circulation. This is scientific speak and I will post something on the different type of antibodies if anybody is interested. Please let me know!
I am slightly surprised that this post or grand challenge has not generated more comments. I suspect it may not be interesting of worrying to the readers of this blog. May be my concerns are unwarranted?I occasionally remind myself that I was one of the people who predicted PML as a complication of natalizumab treatment as well as other CNS opportunistic infections. The one I thought would be a big problem was EBV-associated CNS lymphoma, which has not emerged as a problem.
Not much discussion probably because nobody can do anything about it and because most people dont expect to be on natlizumab very long – they could turn JC+ and be forced to switch, and many are waiting for something safer and effective. People who read your warning are more likely to change when BG12 becomes available.
I wonder if this would be of interest to your haemo-oncology colleagues. There is a problem with leukemic blasts crossing the BB barrier and causing extra medullary disease in the CNS. As MS has borrowed so many drugs from them, perhaps you can return the compliment
In response to Prof G's question about whether people are unconcerned or uninterested – As a MSer who has been on Tysabri for three and a half years and discovered I was JCV+ a year ago, the post has worried and depressed me. As articulated above by another Anonymous poster, what can I do about it ? Do I switch to something else and what would happen to my statistical PML risk ? Do the risks in Prof G's post go away or are the potential neurodegenerative changes a permanent time bomb ? What other long-term side effects from either Tysabri or a drug I switch to may be uncovered as more patient data over longer time periods becomes available ? Is the risk of MS progression and increasing disability greater than any / all of the above ?
I think this is the problem when Prof G argues against the off licence use of other drugs. In most cases MSers who continue to relapse on injectibles are offered natalizumab- maybe this will change as PCT's agree to fingolimod, but what other options do they have at present? And to keep changing these strong drugs, or stopping and starting them, what is it doing to their immune systems?