Extensive intrathecal T cell renewal following hematopoietic transplantation for multiple sclerosis
Kristina M. Harris, Noha Lim, Paul Lindau, Harlan Robins, Linda M. Griffith, Richard A. Nash, Laurence A. Turka, Paolo A. Muraro
Kristina M. Harris, Noha Lim, Paul Lindau, Harlan Robins, Linda M. Griffith, Richard A. Nash, Laurence A. Turka, Paolo A. Muraro
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Research Article Immunology

Extensive intrathecal T cell renewal following hematopoietic transplantation for multiple sclerosis

Abstract

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. Multiple sclerosis pathology is known to be driven by inflammatory T cells that infiltrate the CNS. Therefore, we hypothesized that the preexisting 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 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. More than 90% of the preexisting CSF repertoire in participants with active RRMS was removed following AHSCT and replaced with clonotypes predominantly generated from engrafted autologous stem cells. Of the preexisting 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 preexisting 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.

Authors

Kristina M. Harris, Noha Lim, Paul Lindau, Harlan Robins, Linda M. Griffith, Richard A. Nash, Laurence A. Turka, Paolo A. Muraro

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Figure 2

The preexisting CSF T cell repertoire was substantially removed following AHSCT therapy.

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The preexisting CSF T cell repertoire was substantially removed followin...
(A) TCR overlap percentage was used to determine the percentage of clones that were undetectable (orange) versus detected (gray) by deep sequencing of TCR repertoires in CSF, comparing before therapy to months 24 or 48 for each participant. (B) Number of TCR reads for each clone in CSF before therapy that was undetectable (orange) or detected (gray) in CSF at month 24 for each participant. Percentages correspond to the relative proportion of the TCR repertoire in CSF before therapy in A. (C) Percentage of clones in CSF that were either detected (red) or undetectable (blue) in peripheral blood CD4+ or CD8+ T cells before therapy versus at month 24 after transplant. P < 0.0001, percentage of CSF clones detected in blood at month 0 before therapy versus percentage of CSF clones detected in blood at month 24 after transplant using paired t test. (D) TCR overlap analysis was used to determine the percentage of clones that were undetectable versus detected in the TCR repertoire in CSF before therapy compared with month 24 after transplant, as in A. The percentage of these clones that were detected versus undetectable in pretherapy peripheral blood CD4+ or CD8+ T cells was determined by ultra-deep sequencing, and clones in CSF before therapy were classified into 1 of 4 categories: removed from CSF at month 24 and either undetectable in blood before therapy (gold) or detected in blood before therapy (red); persistent in CSF at month 24 and either undetectable in blood (blue) or detected in blood before therapy (gray). #Participants that met the primary endpoint for the HALT-MS study. All other participants stayed in remission from active MS until the last follow-up.