Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis.
Multiple sclerosis is thought to involve aberrant immune responses to myelin autoantigens. Haematopoietic stem-cell transplantation (HSCT) is in clinical trials for progressive multiple sclerosis based on the rationale that it destroys aberrant immune system, while recapitulation of lymphocyte ontogeny might alter the immune system and slow down disease progression. This study was undertaken to analyse characteristics of the T-cell receptor (TCR) repertoire, serum cytokine profile and the T-cell responses to myelin basic protein (MBP) in the reconstituted immune system in progressive multiple sclerosis. The study revealed that, following autologous HSCT, the T-cell immunity recovered in two distinctive phases. The first phase was characterized by limited T-cell immunity as a result of selective expansion of pre-existing T cells commonly expressing the TCR beta chain variable region (TCR BV) 20 and increased serum cytokine production during the first several months. The second phase of T-cell reconstitution coincided with increased thymic T-cell output 9-12 months after HSCT. T cells reconstituted from stem-cell grafts had the distinctive properties of comprehensive T-cell immunity and a broad TCR repertoire. T cells recognizing MBP were initially depleted by immunoablation and rapidly expanded from the reconstituted T-cell repertoire in 12 months. The reconstituted MBP-reactive T cells exhibited a broader epitope recognition repertoire while maintaining the same skewed reactivity pattern compared with that seen at baseline. The findings have important implications in the understanding of the role of HSCT as a potential treatment for multiple sclerosis.
Sun
Wei
W
Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Popat
Uday
U
Hutton
George
G
Zang
Ying C Q
YC
Krance
Robert
R
Carrum
George
G
Land
Geoffrey A
GA
Heslop
Helen
H
Brenner
Malcolm
M
Zhang
Jingwu Z
JZ
D001324:Autoantigens / Q000276:immunology*; D002455:Cell Division; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D005803:Genes, Immunoglobulin; D006801:Humans; D007135:Immunoglobulin Variable Region; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018655:Lymphocyte Count; D009103:Multiple Sclerosis / Q000276:immunology* / Q000601:surgery; D004676:Myelin Basic Protein / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D013997:Time Factors; D014182:Transplantation, Autologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D001324:Autoantigens; D007135:Immunoglobulin Variable Region; D004676:Myelin Basic Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma