The biggest danger to science is the airbrush

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You write a paper and maybe get 5minutes of fame, but sadly with time this may get forgotten and this may get airbrushed out of history.

Recently, I have been feeling the paint spray as our work on B cells in MS is being forgotten as the big-swingers wake up and tell us all that memory B cells are important, but that gripe is for another day.

Today hopefully you are arriving here by following the “altmetric” link after reading the latest impact factor six offering from the #NIH (National Institute of Health). As a US citizen you not only have the pleasure of paying about $2,000-3,000 for the pleasure of reading this open access work, you have also paid for it. So go on give it a good set of Tweets

Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis. Kasagi S, Wang D, Zhang P, Zanvit P, Chen H, Zhang D, Li J, Che L, Maruyama T, Nakatsukasa H, Wu R, Jin W, Sun L, Chen W.EBioMedicine. 2019. pii: S2352-3964(19)30306-8.

You can read the abstact but they say

“In this study we demonstrated that a combined treatment with transient depletion of T cells together with the administration of neuron derived peptides exhibited both preventive and therapeutic effects in mice with established EAE. The mechanism study revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFβ and together with administered auto-antigenic peptides generated antigen-specific Foxp3+ regulatory T cells (Treg cells) in vivo. “

Implications of all the available evidence

Antigen-specific tolerance is the most specific way of turning off the immune response. It should get rid of disease without causing side effects. The problem in MS is knowing what is the causal antigen, but in EAE this is not a problem and can be done as shown here. Hurray…The cure I hear you say. But we have cured EAE thousands of times and translating this into humans is not that straight forward. As the authors will find out if this approach goes anyhere.

“The results of this study provide an explanation as to why T cell deletion alone failed to efficiently cure the disease, and also provide a new approach to generate antigen specific Treg cells in vivo.”

Let’s read the literature.Is the concept novel and worthy of your hard cash. What does the literature say.

Pryce G, O’Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis.J Neuroimmunol. 2005;165(1-2):41-52 To date there has been poor translation of immunotherapies from rodent models to treatment of progressive multiple sclerosis (MS). In the robust, relapsing Biozzi ABH mouse model of MS, using a combination of a transient deletion of T cells followed by intravenous (i.v.) myelin antigen administration, established relapsing disease in EAE can be effectively silenced. However, when treatment was initiated in late stage chronic-relapsing disease, despite inhibition of further relapses, mice demonstrated evidence of disease progression shown by a deterioration in mobility and development of spasticity and indicates that targeting relapsing, immunological components of MS alone is unlikely to be sufficient to control progression in the late stages of MS.

We were not the first to suggest this approach, it had been reported in the 1960s, but we have done this in humans.

Note to Self-Write this UP!

Many referees have a knowledge base that is a few years old and they fall for the old chestnuts of the sentence “The mechanism is unknown” and “we show this for the first time“. This means to some that you can be a lazy arse and think the work in front of you is wonderful.

I on the otherhand am an old fart. Personally I have these types of comments removed from every paper I review. They are lazy sets of sentences to justify the work and create a view that the work is novel.

They however should be red flags that say “Go and check the literature and you will find that the authors have done a rubbish literature review and that there are plenty of papers”.

This then says to me “If you do your science like your literature reviews, then the science is probably crap too”.

Therefore the authors are misleading the referees and the readers. It is a terrible trait that gets learned. The opinion leaders do it and they get their papers in Nature/Science, Cell etc. Therfore so should I. People are so driven to get there first that they ignore what has gone before. I have written it…but ony when I believed it is the first, but others not so and therefore they airbrush history.

I once penned in a song containing a lyric “”Learn from your history or tomorrow more innocents will die”

In this case it is the beasties who got it and the authours have broken rule number one of ethical science as it shows a total disregard for the #3Rs of animal use. Sadly it seems to be a type of scientific fraud that appears to be deemed to be acceptable.

Indeed, someone this week hopefully will be having the Office of Research Integrity knocking on their door. This week having seen a “This is the first time” sentence. I did a quick search and to my horror I found that the authors had published a paper a year ago that contained 80% of the information in the paper, I was reviewing. They even used the same figures. Is this OK?. Not when you sign up to the view that the work has not been submitted elsewhere. Will the journal do anything?.

So in this current paper they use the chestnut

First, they say “T cell apoptosis is a key to initiating long-term immune tolerance. Our apoptosis process requires transient yet sufficient apoptosis of T cells in vivo”.

Not exactly new but they are using complement fixing antibodies to deplete the T cells so is it apopotois (cell suicide) or killing. Not sure this will be agreed. However apparently what we did >20 years ago we “incompletely understood” as it is all about the generation of CD25+, Fox3P T regulatory cells as a single mechanism of action…..Yawn… as the authors do not realise they are doing the science lemming approach and following the current dogma. Now everything immune is controlled by T regs. In 20 years time when someone next gets their airbrush-out to remove ths paper, the mechansim will be still incompletely undersood and Tregs will have fallen out of favour and the dogma has moved on.

When I first started immune-tolerance the mechanism of this tolerance was CD8 T suppressor cells. This had taken over from B regulatory cells (I predict these will make a come back), this gave way to T cell anergy that gave way to Th2 switch mediated by IL-4, or IL-10 or transforming growth factor beta depending on the lab and then it became T reg driven.

In the current paper, they say “Our study relied on the transient yet sufficient cell apoptosis to initiate the tolerance process, which generated autoantigen-specific Treg cells”. Do they try to disprove it is not T reg driven? Well no. but we don’t do Popperian science any more 🙁 It is science 3 ways (like cooking vegatables three- ways in fine dining). You do the same experiment 3 ways to show the same thing to convince the reviewer/reader it couldn’t be anything else. They say that “It has been reported that antigen pulsed antigen-presenting cells (APCs) chemically fixed with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (antigen stuck to cells/beads etc) could induce antigen-specific tolerance in vivo. The underlying mechanism however remains unknown.”

I know this comment is untrue, as there are are multiple mechanisms that this form of tolerance induces: depletion, anergy and active regulation, etc.

Pryce G, O’Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis.J Neuroimmunol. 2005;165(1-2):41-52

Smith PA, Morris-Downes M, Heijmans N, Pryce G, Arter E, O’Neill JK, ‘t Hart B, Baker D, Amor S.J Neuroimmunol. 2005 Jul;164(1-2):76-84 Epitope spread is not critical for the relapse and progression of MOG 8-21 induced EAE in Biozzi ABH mice.

So we are have being airbrushed. The whole career of someone else from USA has been expunged by this type of sentence. The funny thing was that that person had had selective amnaesia and spent their whole career airbrushing themselves (so ingrained was their paper writing training of ignoring other people, they ignored their own past work. Funnily in doing so, they made every thing they do and have done unbelievable), as they followed the trend of immune tolerance. Yep they eventually said the tolerance was mediated by Tregs….Yawn…Tragic.

The funny thing is the current study cites references from diabetes rather than citing any EAE literature, so the airbrush is on ultrathick setting.

Their history was that they had used an anti-CD3 T cell monoclonal antibody agent to induce tolerance. These agents cause T cells to grow and if you spend a few minutes reading, again you would know that these are not sensible therapeutic agents. Yet a prominent USA professor is proporting just that,…still :-(.

Why is it not a good idea?

Because anti-CD3 makes T cells grow and they create a cytokine storm. Mice live in the dirt and they can tolerate this no problem. A guinea pig getting the same treatment would be dead in 5 minutes. Humans do not do too well.

A similar type of antibody was used, this was called ant-CD28. It makes T cells grow similar to anti CD3 and you may all remember the “Elephant head” scenario when the trial of TGN1412 went wrong and people lost their fingers and toes to gangrene.

In this current study they move on from the anti-CD3 to use both CD4 and CD8 antibodies that are non-stimulatory. CD3 = CD4 & CD8. However, with a bit more reading you may find that the CD8 depletion gets rid of a regulatory T cell that you may actually want to maintain the immune tolerance.

Anyway the moral of the story, is don’t believe everything you read and importantly read round the subject. Knowledge is key. This is very important when you enter trials as not everything is black and white.

It is also important when you are a referee of a paper.

Anyway you ask why I am a Grumpy old soul, Maybe today you get to see an insight of science and that it is not all wonderful as we.may want to portray.

Keeping it Real

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MouseDoctor

9 comments

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  • I strongly agree with not only since I was on both papers but recently I attended a meeting in which someone was trying to induce tolerance in beasties with antigens that don’t even induce T cells. I suggest a history course in science before anyone does any experiments! But then the people on the review boards and those accepting the grants and papers are also to blame!

    • And a course on research ethics…What do we call those who purposely mislead people for gain…Yep this is no different a

  • Cannot understand this. The supervisor of my undergrad project gave me hell for not seeking out the original references for information. How can professionals get away with such sloppiness?

    • I suspect it is not simply sloppiness, but it is choice to ignore. This is a sadly a very common practise, especially from science from certain countries and certain labs.

      Some journals make this easy by restricting the number of references that can be cited. However the real sloppiness lies with the referees.

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