The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 28 February 2005 doi:10.1084/jem.20041679
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 805-816
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ARTICLE

 Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients

Paolo A. Muraro1, Daniel C. Douek4, Amy Packer1, Katherine Chung1, Francisco J. Guenaga4, Riccardo Cassiani-Ingoni1, Catherine Campbell2, Sarfraz Memon5, James W. Nagle3, Frances T. Hakim5, Ronald E. Gress5, Henry F. McFarland1, Richard K. Burt6, and Roland Martin1

1 Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke
2 Information Technology Program, National Institute of Neurological Disorders and Stroke
3 DNA Sequencing Core Facility, National Institute of Neurological Disorders and Stroke
4 Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases
5 Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
6 Division of Immunotherapy, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60208

CORRESPONDENCE Paolo Muraro: murarop{at}ninds.nih.gov OR Roland Martin: martinr{at}ninds.nih.gov

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4+ T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.

Abbreviations used: AUC, area under the curve; CNS, central nervous system; EDSS, expanded disability status scale; HSCT, hematopoietic stem cell transplantation; MRI, magnetic resonance imaging; MS, multiple sclerosis; RTE, recent thymic emigrant; TBI, total body irradiation; TREC, T cell receptor excision circle.


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