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1.
J Exp Med ; 201(5): 805-16, 2005 Mar 07.
Article in English | MEDLINE | ID: mdl-15738052

ABSTRACT

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.


Subject(s)
Multiple Sclerosis/immunology , Multiple Sclerosis/therapy , Receptors, Antigen, T-Cell/immunology , Stem Cell Transplantation , Thymus Gland/immunology , Adult , Amino Acid Sequence , Antigens, CD34/metabolism , Female , Follow-Up Studies , Humans , Immunologic Memory/immunology , Leukocytes/immunology , Leukocytes/pathology , Male , Middle Aged , Molecular Sequence Data , Multiple Sclerosis/pathology , Phenotype , Receptors, Antigen, T-Cell/chemistry , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Thymus Gland/cytology , Transplantation, Autologous , Treatment Outcome
2.
J Virol ; 78(3): 1160-8, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14722271

ABSTRACT

Identification of T-cell subsets that are infected in vivo is essential to understanding the pathogenesis of human immunodeficiency virus (HIV) disease; however, this goal has been beset with technical challenges. Here, we used polychromatic flow cytometry to sort multiple T-cell subsets to 99.8% purity, followed by quantitative PCR to quantify HIV gag DNA directly ex vivo. We show that resting memory CD4(+) T cells are the predominantly infected cells but that terminally differentiated memory CD4(+) T cells contain 10-fold fewer copies of HIV DNA. Memory CD8(+) T cells can also be infected upon upregulation of CD4; however, this is infrequent and HIV-specific CD8(+) T cells are not infected preferentially. Naïve CD4(+) T-cell infection is rare and principally confined to those peripheral T cells that have proliferated. Furthermore, the virus is essentially absent from naïve CD8(+) T cells, suggesting that the thymus is not a major source of HIV-infected T cells in the periphery. These data illuminate the underlying mechanisms that distort T-cell homeostasis in HIV infection.


Subject(s)
HIV Infections/physiopathology , HIV Infections/virology , HIV-1/pathogenicity , T-Lymphocyte Subsets/virology , Adult , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , DNA, Viral/analysis , Female , Flow Cytometry/methods , Gene Products, gag/genetics , HIV Infections/immunology , HIV-1/genetics , HIV-1/isolation & purification , Humans , Immunologic Memory , Lymphocyte Activation , Male , Middle Aged
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