Pharmacologic targeting of T helper (TH) cell trafficking poses an attractive opportunity for amelioration of autoimmune diseases such as multiple sclerosis (MS). MS risk is associated with vitamin D deficiency, and its bioactive form, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to prevent experimental autoimmune encephalomyelitis, a mouse model of MS, via an incompletely understood mechanism. Herein, we systematically examined 1,25(OH)2D3 effects on TH cells during their migration from the lymph nodes to the CNS. Our data demonstrate that myelin-reactive TH cells are successfully generated in the presence of 1,25(OH)2D3, secrete proinflammatory cytokines, and do not preferentially differentiate into suppressor T cells. These cells are able to leave the lymph node, enter the peripheral circulation, and migrate to the s.c. immunization sites. However, TH cells from 1,25(OH)2D3-treated mice are unable to enter the CNS parenchyma but are instead maintained in the periphery. Upon treatment cessation, mice rapidly develop experimental autoimmune encephalomyelitis, demonstrating that 1,25(OH)2D3 prevents the disease only temporarily likely by halting TH cell migration into the CNS.
We have had a topsy turvy week in the world of media and vitamin D. Last week the media was saying it is all a load of tosh following studies in non-MS cases published in the Lancet questioning whether vitamin D is all a myth and that vitamin D had marginal effect on autoimmunity in humans and this week it is the bees knees. Is there any wonder why we do not really know what is going on.
Vitamin D is vital for bone health and can influence immune function and is made in humans following sun exposure. This study was in mice, furry animals who prefer to live in the dark. In this study they gave lots of vitamin D and it stops the development of EAE.
That EAE returns after you stop delivering drug is no big shakes and should be expected to happen.
If you have a decent disease induction protocol (as the antigen depot is there) and the natural regulation that occurs with disease development has not been generated, then disease comes back after a few days or weeks following stopping drug treatment. Unfortunately, this can come as a shock to the people not experienced in the world of EAE. This has led to cancelled clinical trial because of the risk of MS rebound.
This happens with Tysabri and other drugs in MS too
A logical extreme extension of this idea is that vitamin D works in a way similar to Tysabr to block white cells getting in the brain. So it there evidence that sunshine causes PML? (The brain disease that can occur due to stopping white blood cells getting into the CNS)..........Well No.
So the treatment effect is not going to be in the same league as Tysabri. However, to take another extreme with high dose statins we showed that they could inhibit EAE development and could block migration of cells through brain blood vessels because it could inhibit rearrangement of their cellular skeleton. Within two days of stopping drug disease returned (See D below). So what happened in MS? Despite some influence on lesion load in a few studies in MS as shown in EAE studies....the clinical effect has yet to be shown to be earth shattering at the doses used as found in a few studies. So we can go from something ace to it being a damp squib.
In the study they find apparently that it works by blocking a chemokine receptor called CXCR3 (CD182) is reduced, which is a molecule a bit like a stamp that helps it find the brain postcode (ZIP code) by being attracted to molecules that can be produced in MS lesions. Now, what happens in mice were CXCR3 has been removed, well maybe not a lot in some people’s hands and EAE can develop just fine in the absence of CXCR3 following inhibition.
This study suggests that vitamin D works by stopping white blood cells from entering the brain because it reduces a homing receptor. If this is the actual case if should be easy to test. Giving vitamin D to cells in the test tube in humans suggests that there may be an immune modulatory effect, so not quite the same as found in this mouse study. However, you could for example take bloods from any Northern European/American in winter (who will be vitamin D deficient, particularly if they are non-VD supplementing non-whites) show the cells migrate in test-tube assays, now give the person vitamin D to make them vitamin D replete and you should see a major change.
Will it be incremental or Earth shattering?
If vitamin D had such a dramatic impact, there are enough MSers now supplementing with vitamin D for MSers to see a dramatic impact. I personally think that neutriceuticals will have incremental effects, because otherwise they would also come with big side-effects. You may need pharmaceuticals to have major impact. ProfG may think otherwise.
The suggestions that Vitamin D is a risk factor are clear but it maybe has more practical impact in determining whether you will get MS.
Therefore, we should all be ensuring are children are vitamin D replete. This is to my mind where studies should focus. I will be surprised if some clinical trials ongoing will provide useful answers but we will see.
So another bit of Vitamin D in the media last week was questioning whether vitamin D was influencing autoimmunity (in diabetes) in humans. But if you are not doing the right studies are you going to get a useful answer?
You need to ensure you have good bone health to deal with falls and if it limits autoimmunity this is a plus point.
Labels: Vitamin D