Friday, 4 May 2012

Research:Action of Rituximab?

 B cells (cells that produce antibodies) have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. 

However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6-secreting pathogenic (disease causing) B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease than mice with normal B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6-producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell-driven pathogenesis in T cell-mediated autoimmune disease such as EAE and MS.

There is no doubt that treatment of MSers with a B cell depleting antibody can inhibit the development of relapsing disease. But how does this work, is it because it stops the production of damaging antibody?, maybe not  but if not what is it doing. Is it because it is stopping the antigen presenting function of B cells to activate T cells or is it potentially killing a reservoir of virus, such as Epstein barr Virus that lives in B cells.  From looking at mice they beleive that interleukin-6 producing cells may be the target for the rituximab. Interleukin 6 (IL-6) can do many things such as causing fever, but it also facilitates the growth of Th17, which immunologists are causing autoimmunity. Using interleukin six deficient mice they infere that this is the working mechanism of anti-CD20 antibodies such as rituzimab. Then look in MSers and find that some B cells are producing  more IL-6 and this excessive production of IL-6 is lost in B cells from rituzimab-treated individuals. This suggests that rituximab is killing the IL-6 producing B cells. 

Whilst this is feasible explanation, it should be said that the study showed that anti-CD20 treatment only had a very mild inhibitory effect on the neurological course of disease in mice, as has been shown by others with similar antibodies. The influence of anti-CD20 is thus much less marked than the effect that occurs in humans. However, at the time, in relation to disease course of a mouse the study was done, it is known that T cells are inducing most of the action. Inhibition of interleukin6 can have dramatic effects on EAE, but because IL-6 can do many differnt things it may not be the best target for a novel therapy, but it would be a possibility.


  1. 'BCDT ameliorated EAE only in mice with IL-6-sufficient B cells' :
    could something like this be true for MS - that a subset of MSers who produce more IL6 are helped by Rituximab and MSers who produce less don't benefit?

    Prof Larry Steinman says betainterferon helps TH1-type MS and makes TH17-type MS worse (or something on those lines)

    How does that fit in with 'Interleukin 6 (IL-6) ... facilitates the growth of Th17'?
    Does it mean a non-responder to beta interferon is expected to be a responder to rituximab?

  2. Very good comment, I don't know the answer but I would predict that you are on the right track.

    This would be a testable idea and now that the Edinburgh group have shown this effect, then it seems like a logical thing to look at.

    For drug companies peddling drugs it is better to have everyone take it and then determine whether there is effect or not but as there can be significant risks from PML then it is prudent to now if a drug has the potential to work. If we had the answers it would make Neuros lives a lot more productive

    This is sort of related to pharmacogenomics, where the genetic make up of someone may influence the biology of the drugs and determine whether they work or not.

    Is a non-responder to interferon expected to respond to rituximab based on an IL-6 and IL-17 good question I don't know the answer

    Prof Steinman has suggested that beta interferon makes Th1 better and Th17 worse. First point is whether this is actually true, There are people who say no.

    Not all the things Prof Steinman claims turns out to be correct. Tysabri was a success, restricted T cell receptor repertoire was not there are others.

  3. IL-17 and beta interferon responder status bites the dust based on new study fom Biogen and Steinman...So yet another example of unrepeatable stuff. Will post

  4. I have a very crude understanding of medicine but could vaccines create self immunity and rituximab erase the memory of the b cells so to speak the only danger being the cells forgetting how to fight other infections

  5. Re: "I have a very crude understanding of medicine but could vaccines create self immunity and rituximab erase the memory of the b cells so to speak the only danger being the cells forgetting how to fight other infections."

    Yes, vaccines could create self memory, i.e. antibodies against self, but this is very rare. Interestingly, Rituximab has little effect on B-cell memory.


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