#ThinkSpeak: immune rejuvenation therapy

Anti-CD20 vs. the PIRTs, who will win? #ThinkSpeak #MSBlog

Apologies to pwMS who don't have a science background, you may find this post a bit heavy going. However, it is important for you to understand the information in this post as it may inform your decision to be treated with a non-selective, or semi-selective, PIRT (pulsed immune reconstitution therapy), for example alemtuzumab, cladribine or HSCT, rather than going with an anti-CD20 therapy. 

Earlier this week I asked the question whether or not you need a PIRT to deplete both T and B cells, or if you could get away with a simpler B-cell therapy. I made the point that if the Pender hypothesis in relation to EBV is correct then T-cell depletion followed by reconstitution may be important. I have hypothesised that PIRTs may rejuvenate important anti-viral responses, in particular the anti-EBV, CD8+ or cytotoxic T-cell responses, which potentially play a very important role in MS. What is the evidence for this? 

The paper below by Muraro and colleagues on immune function post-HSCT suggest a non-selective PIRT (T & B cells) may rejuvenate your immune system. They show that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. A immune repertoire in this context refers to the diversity of the immune cells in the peripheral blood, in other words how many potential memory T-cells there are to fight infections or cancers. 

In relation to the CD4+ T cells, dominant TCR (T-cell receptor) clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In other words HSCT ablated these clones, which is a good thing if they are responsible for driving autoimmune disease, i.e. MS. 

In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was recreated by clonal expansion of cells present before treatment. What is not answered in this study is whether or not these cells are more responsive to their target, for example against cells infected with EBV. We know that in pwMS the EBV reactive CD8 + cells are senescent, tolerant or burnt-out and simply unable to mount an effective response against EBV. Michael Pender hypothesises that this is the cause of MS, i.e. these cells are unable to enter the CNS (central nervous system) and kill EBV infected B-cells and plasma cells that are driving MS pathology. 

It is important to note that in the study below that patients who failed to respond to HSCT had less diversity in their T cell repertoire early during the reconstitution process. In other words the PIRT did not have the desired effect on rejuvenating the immune system. 

If this hypothesis is correct then anti-CD20, or anti-CD19, or BTK (Bruton Tyrosine Kinase) inhibitors that simply target B-cells may not be the best treatment option for MS. In other words it is not good enough to simply target the EBV reservoir, but we need to rejuvenate the T-cell response to EBV to control MS.

How does a non-specific (alemtuzumab, HSCT) PIRT, or semi-selective PIRT (cladribine), do this compared to a selective B-cell depleter? It is by immunological escape. When the immune system is depleted it allows viral reactivation to occur, i.e. EBV wakes up and starts replicating. We know this happens quite commonly with PIRTs. The viral reactivation is important because it results in viral protein production that then boosts the immune response when the immune system starts recovering. This is like a natural vaccine. This idea is not new and has been muted as a possible treatment for  chronic viral infections, for example in HIV, and underlies the theory of using drug holidays to allow viral reactivation to boost endogenous immunity against the virus.

The implications of this hypothesis are not trivial. If this hypothesis is correct then the anti-CD20's as a class of treatment won't be the treatment of choice for MS, PIRTs (T & B cell depleters) will become the treatment of choice. I therefore urge any researchers reading this post to design and run experiments to test this hypothesis. PwMS won't thank us if they find themselves with progressive brain atrophy and increasing disability 5-10 years after starting an anti-CD20 therapy when they turned down the option of a PIRT early in the course of their MS. 


Muraro et al. T cell repertoire following autolous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar;124(3):1168-72. 

Background: Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. 

Methods & Results: Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCR╬▓ chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. 

Conclusion: These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies.

CoImultiple

Labels: , , , , , ,