Stem cell therapy in multiple sclerosis – no immune re-installation

by Alexey Bersenev on August 4, 2013 · 2 comments

in Uncategorized

Stem cell-based therapy of multiple sclerosis (MS) is a very hot topic. There are a lot of clinical trials going on right now all around the world. Considerably, MS is autoimmune disease, where auto-reactive T-cells enter central nervous system and attack myelin. This auto-aggression leads to inflammation and, eventually, to neurodegeneration. Pathogenesis-based concept behind of stem cell therapy was to halt autoimmune aggression by replacing or inactivating of auto-reactive T-cells. With hematopoietic stem cell (HSC) transplantation, this goal can be achieved by wiping out “diseased immune system” (by conditioning regimen) and “re-installation” of normal – brand new one. That’s where our expectations for mechanisms of action were 15 years ago, when clinical trials just started. But what are we learning from clinical trials now?

It has been very hard to prove “re-installation” of immune system after HSC transplantation. Partly because most of conditioning regimens (not ablative) not allow to distinguish “old persistent” versus “newly developed” auto-reactive T-cells. Also, because autologous hematopoietic grafts in the most trials are not purified and contain T-cells. Finally, we don’t have any studies, where HSC grafts were labeled to lineage-trace cell fate after transplantation. Recent study, published in Annals of Neurology, unveil the real mechanisms of action of transplanted HSC in MS patients.

The authors of this remarkable study, took a cohort of 14 patients with highly aggressive MS, who underwent successful autologous HSC and demonstrated good outcome. The key features of this Canadian trial were (i) immunoablative chemotherapy regimen before transplantation and (ii) CD34+ purified T-cell depleted hematopoietic graft. These settings allowed to identify newly developed T-cells. All patients, analyzed in the study had a “complete abrogation of MS activity” for at least 2 years after HSC transplant. The authors monitored immune system of patients, including myelin reactivity of T-cells before and one year after treatment.

CD3+ T-cells were completely wiped out by chemoablation (as measured in blood) before HSC transplant and didn’t reach a normal level even 2 years after. Surprisingly, the authors did not observe the correlation between good outcome and elimination of auto-reactive T-cells:

Contrary to our initial hypothesis that the sustained abrogation of new disease activity in our patients reflected failure of CNS-reactive T cells to develop in the reconstituting immune system, we documented the re-emergence as well as the in vivo expansion of functional autoreactive T cells capable of responding to multiple myelin epitopes in all treated patients.

So, despite the “clinical absence of MS activity” after stem cell therapy, there was no “re-installation” of immune system. Apparently hematopoietic stem/ progenitor cells have a “memory of disease”. Unfortunately, on the cellular invisible level, MS has not gone away. So, why MS activity has disappeared clinically then? The authors demonstrated that newly developed diseased T-cells are “reprogrammed” and changed functionally:

The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses. Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity…

We don’t know how long this “functional T-cell reprogramming” can last, but it gives us a hint to new potential therapies. For example, if it is the most important mechanism of action in HSC transplant, we can develop smarter drugs to polarize T-cells toward Th17 unresponsiveness. It will allow to avoid highly toxic immunoablation. The significance of balance between regulatory and pro-inflammatory T-cells in MS after HSC transplant was suggested in other clinical studies. Unlike Canadian study, another group has recently reported depletion of auto-reactive T-cells after HSC transplant in non-ablative settings. However, that study was not very well designed. Although, the re-emergence of auto-reactive T-cells after HSC transplant could be different from clinical studies and should be studied further, the lack of Th17 response seem to be universal mechanism.

In case of using mesenchymal stromal cell (MSC) for MS treatment, the mechanisms could be even more complicated. MSC therapy in MS was proposed to suppress auto-aggressive T-cells and inflammation. Expectations for MSC therapy were even higher than for HSC. Because HSC do nothing to neurodegeneration, MSC therapy becomes a “last hope” for induction of remyelination.

Unfortunately, there are very few studies, which assess immune system of patients with MS before and after MSC therapy. The most cited Connick’s study showed no changes in immune status of patients with secondary progressive MS:

Results of weekly blood testing of clinical chemistry, haematology, and immunology during the 4 weeks after infusion was unremarkable. Compared with pretreatment titres, no changes were evident in the post-treatment period for T-cell subset counts (CD3, CD4, CD8, CD19, and CD56) or humoral immunity assessed by titres to common antigens…

However, positive impact on vision gives a hint to potential remylienation.

Yet another recent study did not detect any changes in cytokine profile before and after MSC treatment:

Intrathecal injection of MSCs does not affect cytokine variation in peripheral blood. Because the condition of most of our patients either improved or stabilized after stem cell therapy (SCT), we speculate that the immunomodulatory or neuroregenerative effects of MSC are exerted locally in the central nervous system.

Considering MSC as very powerful immunomodulators, it seem very strange to me that they do nothing to T-cells and blood cytokine profile in MS patients.

{ 2 comments… read them below or add one }

Elizabeth Rebel October 3, 2013 at 3:13 am

Can you tell me how I can find out where these trials are taking place, and when the next one, in, NY, (if possible), will be? My sister in law’s brother has MS.. He is in his 50’s.. and I’m trying to help him. Thank you so very much, Elizabeth Rebel

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Patrick Tracey August 17, 2014 at 5:19 pm

I have MS. Can someone tell me if there is anywhere I can get thus treatment as a clinical trial or otherwise. Please help if you can. I am 52. Thanks

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