It is now dogma that MS is caused by Th17 cells. There is just one problem. Well in fact loads of problems. If you look at the inhibition of Th17 action then the data is not compelling. Inhibition of IL-17 to block Th17 function is rather rubbish in MS. Certain people claim otherwise, but the inhibition of MRI lesions is worse than beta interferon! That doesn’t surprise me because the studies in animals say this approach is rather rubbish.
Am I mad…maybe, but these days it seems a reduction from a score 3 to a score 2.5 is seen as amazing by some people, but I don’t buy it. You shouldn’t either if it is a score of 0 its is interesting half a relapse is still a relapse in human terms. (How does this score occur and this is why we need the raw data) Whilst, I don’t usually report on animal studies, if they are the media or high impact factor journals I do.
So here we have this new paper and what is it trying to say?…Yep new “cure of the week” based on animal models. But take as step back and ask what does it really say…….Actually this approach should be a waste of time in humans. Why? Let’s look at the abstract (I will do a subtext in italics).
Mechanism is all important in most science journals, whereas translational relevance is not questioned, especially if the reviewer is living in the same bubble, with the same beliefs. This must have been hard work dealing with the reviwers as the paper has been under review for 2 years, meaning lots of experiments to satisfy the reviewers. Remember this is just one take of the meaning of the work, it will looked at in many journal clubs around the world, I take a position to say that that you should not accept dogma without some thought.
Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases (Is it really or is this just a dogmatic statement. in the introduction it is said to be controversial hence the need for work). Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis (Is it really? Novartis binned their stuff years ago….Maybe some novarsians can tell the real reason why). In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease (There is a bit literature here, there are loads of studies looking at EAE in TH17, IL17 knockouts. In my book resistant means non-susceptible, relative resistance maybe, but the data shows some disease activity. In studies cited to show resistance we had Komiyama et al. 2006 who reported 100% incidence and Yang et al. 2008 who showed 40-60% incidence in type of mice. This is probably not resistance. Haak et al. 2009 shows minimal impact and so one wonders about the tranlatability in humans) and have defective priming of IL-17-secreting γδ T (γδT17) cells (gamma delta cells are back) and Th17 cells (IL-17 is important for Th17 cells as suggested by Yang et al. 2008). However, T cells from Il17a −/− mice induce EAE in wild-type mice following in vitro culture with autoantigen IL-1β, and IL-23 (Therefore, IL-17 is not essential in disease because you can by-pass it, so is it a good target in MS? ). Furthermore, treatment with IL-1β or IL-17A at induction of EAE restores disease in Il17a −/− mice (The IL-17 is important in the priming or initiation of the immune response. This has happened in MS so why treat after the horse has bolted). Importantly, mobilization of IL-1β-producing neutrophils (These cells are vanishingly rare in MS and any EAE model except in the mouse), and inflammatory monocytes and activation of γδT17 cells is reduced in Il17a −/ mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1β-secreting myeloid cells that prime pathogenic γδT17 and Th17 cells.
But it is the highlights that get me they say:
- •IL-17A is required for priming but not effector function of Th17 cells in EAE(Therefore it says it is absolutely a waste of time targeting IL-17 because you are not going to treat MS before you have MS and has no translational value. We have just shot ourselves in the foot).
- •IL-17A-defective mice are highly resistant to induction of EAE—rescued by IL-1β (So any infection etc. that makes IL-1 is going to counteract this mechanism, so is it a good target in MS?)
- •IL-17A acts in a positive feedback loop to induce IL-1β production early in EAE (OK but so what)
- •IL-17A-induced chemokines mobilize IL-1β-secreting neutrophils and monocytes (However, neurophils are not a real issue of MS but may be be more common in NMO,so the model lacks translational value)