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. 2020;5(2). pii: 127655.
A recent study of autologous hematopoietic stem cell transplantation (AHSCT) for active relapsing-remitting multiple sclerosis (RRMS) showed efficacy in preventing disease worsening. However, the immunologic basis for efficacy remains poorly defined. (Dogma Alert!!!!!) Multiple sclerosis pathology is known to be driven by inflammatory T cells that infiltrate the CNS (I wonder if anyone (referee) said what about the B cells:-). I doubt it). 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 (If disease was inhibited, why would you expect any cells to survive in the CNS if disease is inhibited?). T cell repertoires were assessed using high-throughput TCRβ chain 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. (Again, surely if there is ablation of the immune response, we should not expect the repertoire to be replaced. It should be ablated and there should be no cells to tissue type). More than 90% of the pre-existing CSF repertoire in participants with active RRMS was removed following AHSCT and replaced with clonotypes predominantly generated from engrafted autologous stem cells (However, as disease is gone we would expect the number of cells to drop, but if 90% of the repertoire drops, I would say we would expect 90-95% of the repertoire to go as 90-95% of the cells in the CNS are disease irrelevant they are drawn in by 5% of the disease related cells). Of the pre-existing clones in CSF, approximately 60% were also detected in blood before therapy, and concordant treatment effects were observed for clonotypes 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.
The suggestion is that cells go from the peripheral blood into the brain to cause MS attacks…wow. I wouldn’t have guessed that :-). Essentially all MS treatments that affect MS, including HSCT, limit the ability of peripheral blood cells to get into the CNS, so I would be surprised if this was not found
In the cohort of 24 participants that underwent AHSCT, 17 achieved durable complete remission from active disease, 3 experienced clinical relapse, 2 showed disease progression by increased Expanded Disability Status Scale, and 2 had recurrence of CNS inflammation detected by MRI through the 60 months follow-up.
Most of the preexisting CD4+ T cell repertoire in blood before therapy was undetectable following transplantation at months 12, 24 and 48 (mean 81.4% ± 7.4% SD at month 12; mean 83.8% ± 5.5% SD at month 24; mean 88.7% ± 4.7% SD at month 48. This suggests that new cells are coming from the bone marrow/stem cell transplant
The majority of T cells detected in CSF before therapy were undetectable in CSF at months 24 and 48 after transplant. On average, 91.8% (±7.2% SD) and 93.5% (±6.9% SD) of the preexisting CSF repertoire was undetectable in CSF at 24 and 48 months, respectively. These data indicate that most of the preexisting TCR repertoire in CSF was removed by AHSCT irrespective of the clones’ individual frequency and show that the effects are durable through 48 months follow-up.
>90% of the T cell repertoire in CSF before therapy was undetectable at months 24 or 48 after AHSCT therapy. The majority (80.3% ± 14.2% SD) of T cells detected in CSF at month 24 were undetectable in the CSF before therapy, indicating that most of the reconstituted repertoire in the intrathecal compartment comprised new species of T cell clones. This indicates that disease is not completely inhibited. They found that >40% of the removed CSF repertoire consisted ofcell types that were exclusively detected in CSF (i.e., which were undetectable in peripheral blood T cells) of active RRMS patients before therapy.
However, the question I would ask is what happened to the people where disease was not inhibited.
Next point, as I am playing devil’s advocate ….if the pathogenic population was in the B cell compartment, then this study is looking in the wrong place. We would say who cares about what happens in the T cells you are missing the point! Likewise, we could say what happens if the interesting cells are a subset of T cells then the analysis is muddying the water, So I have given this post a Medical Fiction link:-)