Here is a new offering from the CLAD lads :-), and follows on from the information that we got from the European Medicines Agency and from stuff in the public domain. This is not a pharma supported piece of work and they may have different views of how cladribine works or how they want to portray how they think this works, but as usual for us, it contains ideas of the unknown. Things we and importantly they can and should test.
This is our take on how cladribine may be working…it may be wrong, but it incorporates available data and does not follow the Treg-control of every thing dogma. It puts the T cell dogma into the perspective of the B cell reality….Ha Ha:-).
Some people may not be happy, as we have mentioned the content of published abstracts that they were on, but have not published, and interpreted their conclusions in a different way. Yep, there is now no need for them to waste paper as the essential information is out in a way that makes more sense:-).
I can see the moaning email winging its way to DrK.
You will notice this does not include ProfG, who will see this manuscript here for the first time too. He is a lead on the pharma view and we were sneaky and got and published the stuff that he could have published. So this way ProfG does not get his hands dirty. He may have additional takes on this story, as he has the inside information and insight that we don’t.
As to the people who may be upset…… “You snooze, you lose” they have have had ample time to publish the findings. Too much time going to meetings on pharma coat tails and not enough time writing I guess:-(.
Importantly this manuscript contains stuff that it appears academics seem to fear the most….Yep Opinion and Speculation. No wonder we get so many reviews that are a ramble of unrelated, supposed, facts that lack any insight:-(. This of course means that we get alot of scientific headless chickens running around
We have met this fear and need to accept and pacify dogma time and time again during the review process.
It suggests to me that many of these scientists would make terrible police officiers.
Why? They can see a dead Dr Black (UK)/Mr Body-John Doe (US) with a big knife in their back and a blood trail from the study. However, they are too frighened to say that the knife killed Dr Black, unless they see the video of it happening. Unfortunately nobody was there with a smart phone to do this, so they would you have to look at the evidence. God forbid that they could suggest that it was Colonel mustard, who did it in the study (Cluedo). Yet they are happy to accept and suggest that Dr Black dies from food poisoning, because of an altered microbiome, because that is what everyone else thinks should happen. They are happy to ignore the machete. in search of the antibiotic, whilst ignoring the problem with knife-crime. Sad thing is…they would have to stick a machete into someone to show that it can be a lethal weapon, before they can believe it.
DO NOT PAY FOR THIS ARTICLE!. IN A FEW DAYS I WILL POST A LINK THAT WILL GIVE YOU FREE ACCESS
Multiple sclerosis & Related Disorder
Oral cladribine is a novel treatment for relapsing multiple sclerosis (MS). This appears to be a semi-selective immune-reconstitution therapy that induces long-term therapy from short treatment cycles. It has a relatively good safety profile that currently does not require extensive monitoring associated with some continuous immunosuppressive and relatively non-selective immune reconstitution therapies. The efficacy and safety of cladribine relates to its particular physicochemical properties, the function of the lymphocyte subsets that are selectively targeted by the drug and the repopulation kinetics of these subsets. As such, there is marked and long-term depletion of memory B cell subsets, which probably relates to the therapeutic efficacy. This is also coupled with a more limited, but likewise long-term, depletion of CD4 T subsets. There is limited depletion of cells of the innate immune system and modest effects on CD8 and probably plasma cells, which provide immediate and durable protection from infection. Targeting of CD4 T regulatory cells, CD8 T suppressor cells and regulatory B cell subsets appears more limited as these populations recover rapidly and so repopulating pathogenic cells re-emerge into a regulatory environment. This appears to lead to re-establishment of immune-tolerance that produces long-term control of MS. Although this hypothesis contains a number of unknown details, it is based on knowledge about the biology of cladribine, basic immunology and the effects of other high-efficacy B and T cell depleting agents that exhibit stereotyped repopulation behaviours. These concepts are relatively simple to interrogate, and can be modified as new knowledge about the durability of disease control and safety with cladribine emerges.