Cladribine depletes memory B cells…But Hey. So do a number of MS treatments

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What happens to T and B cells after oral cladribine. This has all been reported for T cells before…so who cares…..Only joking, However we know what will happen. T cells drop by 50% in year one and more in year 2. However, this study points the finger away from CD20 T cells that some people are so desparate to show how ocrelizumab works. Th17 T cells drop and there is a suggestion that at latter time points there is a drop that may increase risk of infection….I am sure the manufacturers would argue, where is the data?

Cell numbers after cladribine CD14 = monocytes

However, what about B cells. I would imagine something similar to the influence of subcutaneous cladribine. We showed that memory B cells were depleted for at least a year and we have been waiting for the manufacturers to replicate and expand on this data…they have been done and should have finished (May 2020) a study in 270 people (NCT03364036) study called MAGNIFY.

But snooze and you loose and you can get an answer with fewer people at the 270 person study becomes less interesting…This one looks at 18 people. They found that CLAD strongly reduced memory B cell (CD19+CD27+) counts at the end of year one and two respectively. Early on (months 3 and 15) antigen experienced B cells (CD27+) were depleted by at least 94%. CD19+CD27+IgD-,IgM class-switched memory Bcells (-78%) and (- 87%) for months 12 and 24, respectively. Plasmablasts (CD19+CD38++CD10-) were apparently signicantly depleted following administration but CD138+ plasma cells were apparently not signifcantly affected, although their numbers seems to drop, but there are very few in the blood. So this is relevant for what may happen to oligoclonal bands and suggests there may not be a quick drop..

There is an increase in B regulatory and T cells early after treatment. Is this why cladrinbine works. Some people call them immatre B cells other people call them transitional cells

memory B cells drop after cladribine. Bregs go up whats important

Moser T, Schwenker K, Seiberl M, Feige J, Akgün K, Haschke-Becher E, Ziemssen T, Sellner J. Long-term peripheral immune cell profiling reveals further targets of oral cladribine in MS. Ann Clin Transl Neurol. 2020 Oct 1. doi: 10.1002/acn3.51206.

Objectives: To expand the knowledge about the immunological consequences of cladribine (CLAD), a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS), beyond the known short-term effects on peripheral immune cell subsets.

Methods: In this study, we characterized depletion and restitution kinetics as well as cytokine profiles of peripheral immune cell subsets in 18 patients with MS following treatment with oral CLAD. The methods involved blood collection prior to CLAD and every three months over a period of 24 months, and extensive characterization of various immune cells subsets by multiparametric flow cytometry.

Results: We found a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper-repopulation of maturing B cells. Counts of classical (-65%) and various nonclassical TH17 cells (-84% to -87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of class-switched memory B-cell phenotypes (-87% to -95%). The nadir of TH cells was more pronounced in the second treatment year. We observed a proportional surge of CD20 T-cell subsets and an expansion of regulatory T, B and NK cells. Natural killer T cells (NKT) were only depleted in year two and did not recover.

Interpretation: Peripheral immune cell profiling revealed more differentiated insights into the immunological effects of CLAD. While some immune cell subsets expanded, we also observed additive depleting effects after the second treatment course. Further studies are required to elucidate whether these changes are paramount for the consistent and prolonged disease-modifying effect of Cladribine

There is nothing special about what happens to B cells. it is a stereotyped behaviour that occurs with other agents that deplete B cells . For example rituximab Don’t believe me, well another paper on B cell depletion and repopulation has been published by Nissimov N, Hajiyeva Z, Torke S, Grondey K, Brück W, Häusser-Kinzel S, Weber MS. B cells reappear less mature and more activated after their anti-CD20-mediated depletion in multiple sclerosis. Proc Natl Acad Sci U S A. 2020 Sep 30:202012249. doi: 10.1073/pnas.2012249117. This repeats the work of Palanichamy et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J. Immunol. 193, 580–586 (2014). Reference 26

Nissimov et al. B cell depletion via anti-CD20 antibodies is a highly effective treatment for multiple sclerosis (MS). However, little is known about the maturation/activation stage of the returning B cell population after treatment cessation and the wider effects on other immune cells. The Editor and the authors should have gone to Spec Savers and read their reference 26:-). In the present study, 15 relapsing-remitting MS patients receiving 1,000 mg of rituximab were included. B, T, and myeloid cells were analyzed before anti-CD20 administration and in different time intervals thereafter over a period of 24 mo.

In comparison to the phenotype before anti-CD20 treatment, the reappearing B cell pool revealed a less mature and more activated phenotype: reappearing B cells were significantly enriched in transitional (before: 10.1 ± 1.9%, after: 58.8 ± 5.2%) and the frequency of memory B cells was reduced (before: 36.7 ± 3.1%, after: 8.9 ± 1.7%); and 3) reappearing B cells showed an enhanced expression of activation markers CD25 (before: 2.1 ± 0.4%, after: 9.3 ± 2.1%) and CD69 (before: 5.9 ± 1.0%, after: 21.4 ± 3.0%), and expressed significantly higher levels of costimulatory CD40 and CD86. T cells showed a persistent increase in naive (CD4+: before: 11.8 ± 1.3%, after: 18.4 ± 3.4%; and CD8+: before: 12.5 ± 1.4%, after: 16.5 ± 2.3%)

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  • Interesting stuff Mouse Doctor….a few questions for you.
    I am a doctor with MS. I had PML/IRIS last year (JCV +ve/tysabri), it was all pre symptomatic seemed to settle with steroids and immune reconstitution. Finished steroids in Dec and continue on copaxone. My MS is good and I’m going well on keto (that’s a different story, I’ll save those tales for Prof G).
    My neuro is talking about cladribine should I need a stronger DMT in the future, what are your thoughts on that post PML? In fact what are your thoughts on which DMT you would go for post PML? On a pathological front what do you think happens to my mutated JCV – is it cleared by immune reconstitution, is it sitting in a latent pool somewhere ready for resurgence at any opportunity or it it that I just maintain the potential for further mutations/PML……? I know there may not be clear answers to this but I’d be curious what your thoughts are? Thank you

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