ECTRIMS2021. The CD20-gurus says that ocrelizumab/rituximab works because of an effect on CD20 T cells…It’s T time

E

If you talk about B cells in MS there are two names that pop-up over and over again. Guru I from the West-side and Guru II from the East-side. No this is not me in the East End of London.

Members for Guru II’s lab have been asking “How does ocrelizumab inhibit MS?”…….My simplistic easy view is that ocrelizumab depletes pathogenic B cells. However it seems that it is in fact a T cell that is the problem.

“Yeah” say the T cellers… “we always knew this was the case.” Indeed if you do not mention this as a possibility…no a probability….your B cell papers are going to stuggle to get published.

However, I wonder why do you select a difficult-ask and exclude the obvious? I ask why was nothing done to disprove the obvious, but it wasn’t. In this current study the B cells were just CD19+ B cells but the T cells were subdivided into lots of lovely T cell subsets when it was asked why do some people show disease activity shortly after treatment with ocrelizumab….This study suggests that this correlates in particularly with CD20+ T cells.

ECTRIMS 2021Shinoda et al. 189 – Cellular immune profiling pre- and post-aCD20 therapy points to differential effects on CD4+ and CD8+ T cells and implicates CD20-expressing CD8+ T cells in MS disease activity

Introduction: While the humanized anti-CD20 (aCD20) monoclonal antibody ocrelizumab is highly efficacious in limiting new MS disease activity, a small proportion of patients develop new disease activity early (typically 3–6 months) after treatment and then remain in remission with ongoing treatment. Assessing early cellular immune profiles and their association with such transient disease activity may provide a window into MS relapse biology.
Methods: Phenotypic and functional immune profiles were comprehensively assessed by multi-parametric flow cytometry in high-quality cryopreserved PBMC obtained from two independent, well-characterized (Discovery and Validation) MS cohorts, prior to and following ocrelizumab initiation and analyzed in relation to disease activity.
Results: The single-center Discovery cohort recruited patients with RRMS and PPMS, never previously exposed to disease-modifying therapy (n=23), while the multi-center Validation cohort focused on 35 patients with RRMS. Anti-CD20 initiation decreased both CD4+ and CD8+ effector memory, pro-inflammatory cytokine-producing and central nervous system (CNS)-trafficking T cells, and mediated the predicted depletion of T cells expressing CD20 (all confirmed in the validation cohort). Treatment-associated changes in pro-inflammatory CD8+ T cells could be fully explained by removal of pre-treatment CD20-expressing CD8T cells, while treatment-associated changes in pro-inflammatory CD4T cells could only partially be attributed to direct removal of pre-treatment CD20-expressing CD4+T cells. Remarkably, lower pre-treatment proportions of circulating CD20-expressing CD8T cells were strongly correlated with the numbers of pre-treatment Gadolinium-enhancing lesions, and also associated with early disease activity observed after aCD20 initiation.
Conclusion: Our study provides novel insights into both the mode of action of aCD20 and mechanisms underlying MS relapse biology. We distinguish the impact of aCD20 on CD8T cells (largely direct removal of CD20-expressing cells), versus the impact of aCD20 on CD4T cells (a combination of direct removal, and indirect effects, presumably through depletion of B cells resulting in their diminished in vivo interactions with the CD4T cells). The strong inverse correlation with disease activity suggests that CD20-expressing CD8T cells leaving the circulation (possibly to the CNS) participate in early encephalitogenic events involved in MS relapse development.

So if this is true I guess the authors should focus their attention on these cells to tell us how they do this and what they are reactive too. They should not flip-flop to other targets. Surely if you know where to look, you can get the answer.

They have “set out their stall”. It is evident that most CD20 T cells are CD8 positive and not CD4 positive. So I ask “Have Th17 (CD4) T cells had their day too”……I guess the focus should be why CD20 T cells are the issue. If they don’t then one suspects they are not convinced in their own story

Guru 1 has said CD20, CD8 T cells react to myelin basic protein.

Sabatino J et al. Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25800-25807.

So this is the answer, its the CD8 T cells!!!.

Should we develop a CD8 depleting T cell approach? I would be very cautious about this but it is a logical choice can the gurus convince Pharma?

I guess we should ask how do we disprove this view (Popperian Science…You can’t prove an idea but you can disprove it). In this ECTRIMS2021 study they replicated their own work and approach. Is that proof?.

I ask myself about anti-CD19. It is active like anti-CD20 in MS, but T cells essentially don’t express CD19. So how does this work is there an extra special tweenie-weenie subset? Do the other MS drugs target this subset?

Seems the answer for DMF, Fingo is not very well and for natalizumab it seeems to increase them. I guess it is the same answer for memory B cells too. What are the killer experiments to do?. What do you think?

Quendt C et al. Proinflammatory CD20+ T Cells are Differentially Affected by Multiple Sclerosis Therapeutics. Ann Neurol. 2021 Sep 13. doi: 10.1002/ana.26216

Anti-CD20 treatment virtually extinguished CD20+ T cells, which might explain its broad effectiveness. Dimethyl fumarate dampened activity of differentiated CD20+ T cells, whereas fingolimod reduced their abundance only as part of its overall T cell suppressive capacity. Natalizumab increased the frequency of CD20+ effector T cells. Widely used MS therapeutics affect this proinflammatory T cell subset with assumed pathogenic potential in a surprisingly differential manner. 

If it is is CD20 CD8 T cells that are important would DMF be a better treatment than fingo?

COI Multiple

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

About the author

MouseDoctor

8 comments

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives