This is open access so for those interested, you can have a read. It says efficacy of HSCT is associated with lost of T cells from the CNS. I guess we could have guessed that this would happen, and one would suspect it should happen with any treatment that works. The study also serves to show that most people don’t give a monkey’s about B cells. Mention only T cells and there is no problem. Maybe there is another paper on the way
Extensive intrathecal T cell renewal following hematopoietic transplantation for multiple sclerosis. Harris KM, Lim N, Lindau P, Robins H, Griffith LM, Nash RA, Turka LA, Muraro PA. JCI Insight. 2019 Dec 26. pii: 127655. doi: 10.1172/jci.insight.127655. [Epub ahead of print]
A recent study of AHSCT for active relapsing-remitting multiple sclerosis (RRMS) showed efficacy in preventing disease worsening. However, the immunologic basis for efficacy remains poorly defined. MS pathology is known to be driven by inflammatory T cells that infiltrate the central nervous system (CNS). Therefore, we hypothesized that the pre-existing T cell repertoire in the intrathecal compartment of active RRMS participants was ablated, and replaced with new clones following AHSCT. T cell repertoires were assessed using high-throughput T cell receptor sequencing sequencing in paired cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T cells from participants that underwent AHSCT, before and up to 4 years following transplantation. >90% of the pre-existing CSF repertoire in participants with active RRMS was removed following AHSCT, and replaced with cells predominantly generated from engrafted autologous stem cells. Of the pre-existing clones in CSF, ~60% were also detected in pre-therapy blood, and treatment effects were observed for cells in both compartments following AHSCT. These results indicate that replacement of the pre-existing TCR repertoire in active RRMS is a mechanism for AHSCT efficacy, and suggest that peripheral blood could serve as a surrogate for CSF to define mechanisms associated with efficacy in future studies of AHSCT.
This study looks at the T celll diversity and concludes that as this is wiped out from the brain. Therefore this is the mechanismof action. However, these repetoires will also be removed from the blood, so they can’t get in the brain. Is this the real mechanism? In many cases the HSCT protocol has limited effects on events in the CNS and so the influences may be secondary to effects elsewhere. However, if disease is being irradicated it will be associated with loss of immune function in the CNS. This is what was found here.
If we look at studies where we know what is causing the lesions, we find that the majority of the cells accumulating in the CNS, have nothing to do with the the disease causing cells and are pulled into the inflammed CNS by virtue of their adhesion molecules, chemokine receptors etc etc. Indeed less than 5% of may be specific for the target. In this study 90% of the repertoire is replaced, meaning that 10% is not. This could be enough to allow for disease breakthrough.
The question we have to ask is, what are the engrafted T cells (i.e. those coming from the HSCT) doing in the CNS. If disease is effectively dealt with you would be hoping not to find them. However there is no qunatitation here and I guess before HSCT there was not much of a problem finding cells to assay, after it is going to be more of a problem.
In this study the repertoire of CD4 T cells dropped by about 80-85% but the CD8 repertoire dropped by about 70% (many of which will be against viruses). About 90% of the T cell repertoires detected in the CNS before HSCT was gone. 60% of the cells detected in the CNS were present in the blood. However the big question is what happened to people who showed disease reactivation, indicating that HSCT had not been successful
However, the study confirms what we know that HSCT is pretty good at depleting immune cells and this is how it works