They did two models and they both work. So now we have a prime candidate for a trial.
Will it happen? Maybe.
However has the best candidates been thrown away?
This was a systematic approach, but as the authors point out there are limitations
1. They focused on three features of progressive MS which included immune cell proliferation.
We know EAE is T cell mediated and when tested at a dose over ten times the human dose there was some inhibition of EAE. It was about 3-4 times times the human dose based on blood levels, although it was argued they are similar. Maybe a dose-response would have shown us what dose mediates a positive effect.
However, we have shown a number of times that T cell inhibition does not inhibit progressive EAE. This is not apparent in a few days of observation, as done in this study, it develops of weeks and months.
Importantly, we have done trial after trial after trial of T cell inhibitors on progressive MS and they have failed, failed and failed again.
HSCT is the ultimate example and it is evident that once started progression will continue (I am not say it has no effect), because the processes that are driving this response are not dependent on T cells. There is no mention of the clinical reality.
2. They selected one fixed dose to do the screening. The dreaded 10 micromolar. For many compounds that are highly fat soluble (which is often the case for CNS penetrating drugs) this is the dose just before cells turn up their toes and die and many drugs do stuff at this dose and nothing much useful at clinically relevent doses. Don't believe me..read the cannabinoid literature...it is full of such nonsense.
In this study they used 10 micromolar (3150ng/mL) and got 100% protection against iron toxicity.
Now if we look at the steady state blood levels of a standard dose and the mean is around 150ng/ml This is therefore about 0.5 micromolar. However, they did a dose response and found some activity as human plasma levels. In the mice clomipramine accumulated in the brain to over twenty times the level in the blood.
Importantly clomipramine is rapidly broken down to demethyl-clomipramine, which is pharmacologically active and participates in both therapeutic and unwanted effects. So this should have been tested to look for the drug effects.
The clinical reality is largely ignored.
Surely drugs should not be tested above doses that are likely to occur in humans, otherwise we are likely to get false positives.
Secondly identifying the key mediators of progressive MS is key for any drug screening. People have their favourites, however, I personally do not think that T cell proliferation activity is something we should be bothering with.
Do you disagree?
I think T cells have to proliferate and expand in number to create immunity but once effector cells are formed, do they need to proliferate to be active in the brain?
Can they simply secrete cytokines and other factors to do their job and then die, After all we can make new ones from memory cells in the lymphoid tissue.
Do EAEers have T cell-coloured glasses on. I think so.
Iron is found in MS lesions, EAE is mediated by T cells....therefore iron causes T cells to induce autoimmunity....QED.
iron promotes T cell pathogenicity by protecting RNA -binding protein PCB P1 from breakdown promoting stabilization of a cytoine GM-CSF, implicated in inflammation
Wang Z, Yin W, Zhu L, Li J, Yao Y, Chen F, Sun M, Zhang J, Shen N, Song Y, Chang X. Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production. Immunity. 2018 Jun 21. pii: S1074-7613(18)30244-9. doi: 10.1016/j.immuni.2018.05.008. [Epub ahead of print]
Iron deposition is frequently observed in human autoinflammatory diseases, but its functional significance is largely unknown. Here we showed that iron promoted proinflammatory cytokine expression in T cells, including GM-CSF and IL-2, via regulating the stability of an RNA-binding protein PCBP1. Iron depletion or Pcbp1 deficiency in T cells inhibited GM-CSF production by attenuating Csf2 3' untranslated region (UTR) activity and messenger RNA stability. Pcbp1 deficiency or iron uptake blockade in autoreactive T cells abolished their capacity to induce experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Mechanistically, intracellular iron protected PCBP1 protein from caspase-mediated proteolysis, and PCBP1 promoted messenger RNA stability of Csf2 and Il2 by recognizing UC-rich elements in the 3' UTRs. Our study suggests that iron accumulation can precipitate autoimmune diseases by promoting proinflammatory cytokine production. RNA-binding protein-mediated iron sensing may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.
The only problem here is if B cells are the important cell type how do we build this data into a reality?