Brain Advance Access originally published online on February 25, 2004
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Brain, Vol. 127, No. 5, 996-1008, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh117
Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis
1 Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, 2 Gene and Cell Therapy Center, Department of Medicine, 3 Department of Pathology and 4 Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Correspondence to: Dr Jingwu Zhang, Department of Neurology, Baylor College of Medicine, 6501 Fannin Street, NB302, Houston, TX 77030, USAE-mail: jzang{at}bcm.tmc.edu
*These authors contributed equally to this study
Multiple sclerosis is thought to involve aberrant immune responses to myelin autoantigens. Haemato poietic 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 ß 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.
Key Words: haematopoietic stem-cell transplantation; multiple sclerosis; myelin basic protein; T-cell receptor
Abbreviations: CDR3 = complementarity-determining region 3; EDSS = Expanded Disability Status Scale; ELISA = enzyme-linked immunosorbent assay; ELISPOT = enzyme-linked immunospot assay; HSCT = haematopoietic stem-cell transplantation; Ig = immunoglobulin; IL = interleukin; MBP = myelin basic protein; PBS = phosphate-buffered saline; TCR = T-cell receptor; TCR BC = T-cell receptor ß chain constant region; TCR BV = T-cell receptor ß chain variable region; TREC = T-cell receptor rearrangement excision circles
Received November 4, 2003. Revised December 16, 2003. Accepted December 18, 2003.
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