Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A

Namita Misra; Jagadeesh Bayry; Anastas Pashov; Srini V. Kaveri; Roseline d’Oiron; Natalie Stieltjes; Valeri Roussel-Robert; Michel D. Kazatchkine; Olivier Boyer; Sébastien Lacroix-Desmazes

doi:10.1160/TH03-05-0300

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2003; 90(05): 813-822
DOI: 10.1160/TH03-05-0300

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A

Namita Misra

¹INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France

,

Jagadeesh Bayry

¹INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France

,

Anastas Pashov

¹INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France

,

Srini V. Kaveri

¹INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France

,

Roseline d’Oiron

²Centre d’Hémophiles, Hôpital Bicêtre, Paris, France

,

Natalie Stieltjes

³Centre des hémophiles, Hôpital Cochin, Paris, France

,

Valeri Roussel-Robert

³Centre des hémophiles, Hôpital Cochin, Paris, France

,

Michel D. Kazatchkine

¹INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France

,

Olivier Boyer

⁴Laboratoire de Biologie et Thérapeutique des pathologies immunitaires, CERVI, Hôpital Pitié-Salpêtrière, Paris, France

,

Sébastien Lacroix-Desmazes

¹INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France

› Institutsangaben

Abstract

Summary

In the present study, we have analyzed the T cell receptor (TCR) repertoires of CD4+ T cells isolated from peripheral blood of 10 inhibitor-positive patients with severe hemophilia A. The distribution of complementarity determining region (CDR3) lengths of the beta chain of the TCRs was analyzed by spectratyping prior to and following in vitrostimulation of the cells with human factor VIII (FVIII). The repertoires of CD4+ T cells of patients were perturbed when compared to those of healthy blood donors. The perturbations of T cell repertoires were heterogeneous among patients with respect to the number and the nature of V-beta (BV) families that exhibited expansion following incubation with FVIII. Some patients showed alterations in one or two BV families, others exhibited more perturbed repertoires affecting 5 to 8 of the 14 BV families tested. Alterations of BV2, BV5 and/or BV9 were consistently found after incubation of CD4+ T cells in the presence of FVIII in 80% of the patients. These findings indicate that the presence of FVIII inhibitors in patients with severe hemophilia A is associated with measurable perturbations of the CD4+ T cell repertoire that results from oligoclonal expansion of FVIII-specific cells and may be relevant for the design of strategies aimed at modulating the anti-FVIII immune responses by T cell-targeted therapy

Keywords

Hemophilia A - FVIII Inhibitor - T lymphocytes - T cell-receptors - Repertoire development

Volltext

Referenzen

References
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