Friday, 11 December 2015

ResearchSpeak: B cell depletion and immune tolerance

Anti-CD20 treatment is not the holy grail for treating autoimmune disease. #MSResearch #MSBlog #ResearchSpeak

"The Type 1 diabetologists are way ahead of us in that they have a very good idea of what autoantigens are driving their disease. The study below shows that B cell depletion with rituximab in type 1 diabetes only has a temporary impact on autoimmune B cell responses. The autoreactive cells bounce back quickly post-rituximab treatment. In short anti-CD20 therapies are not the holy grail when it comes to treating autoimmunity. This would be consistent with the experience of anti-CD20 therapies in MS and makes a case for using anti-CD20 treatments as a maintenance treatment, i.e. given continuously, rather than an induction treatment. The real questions that will be need to be answered ASAP; does maintenance anti-CD20 treatment prevent progressive MS?"


Epub: Chamberlain et al. Rituximab does not reset defective early B cell tolerance checkpoints. J Clin Invest. 2015 Dec 7. pii: 83840. doi: 10.1172/JCI83840.

Background: Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti-B cell therapy thwarts autoimmunity in these pathologies. 

Objective: Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. 

Results: We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. 

Conclusions: We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy.

CoI: multiple

9 comments:

  1. So Ocrelizumab would also have to be given continuously? Also for progressive MS?

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    Replies
    1. Yep, that's what these results suggest.

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    2. Instead of continuous ant-CD20 why not consider myeloablative stem cell therapy? I know many consider the risks too great but the technology has improved and has the safety. The cost of continuous peripheral ablation of B-cells would probably exceed this one time procedure. For aggressive case of MS this may make sense.

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    3. "Yep, that's what these results suggest."

      What? This is a pretty naive interpretation of these results. We can't even reliably translate results from NMO to MS. Why think that this finding in diabetes has any bearing on the biology of MS?

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    4. The decision about what makes more sense will depend on the side-effect profile and the ability to prevent the progressive phase

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  2. Is this relevant in respect of Lemtrada?

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  3. " Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion".

    The question is what is driving the newly generated B-cells? Anti-CD20 therapy does not appear to address the root cause ...

    ReplyDelete

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