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
View: Text | PDF
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

×

Figure 5

CMV infection after AHSCT therapy is associated with impaired TCR diversification and an increased ratio of memory-to-naive cell subsets in circulating T cells.

Options: View larger image (or click on image) Download as PowerPoint
CMV infection after AHSCT therapy is associated with impaired TCR divers...
(A) TCR repertoire diversity was analyzed using the Shannon entropy index in blood CD4+ and CD8+ T cells before therapy and at months 12, 24, and 48 after transplant. (B) Ratios of circulating CD4+ (top) and CD8+ (bottom) central memory (Tcm) and effector memory (Tem) to naive (Tn) cells were analyzed by flow cytometry, as previously reported (13). Filled triangles represent participants that met the primary endpoint for the HALT-MS study before month 60 after transplant, and open circles represent participants that stayed in remission from active MS until the last follow-up. Participants were further stratified based on CMV infection status after transplant. Black shapes represent participants that were CMV– and red shapes represent participants that were CMV+ by PCR after transplant. The lines represent the mean of all participants evaluated at each time point. *P < 0.05, between month 0 before therapy versus months indicated after transplant using mixed model for repeated measures. ¥P < 0.05, between CMV+ versus CMV– groups after transplant at each visit using mixed model for repeated measures.