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
1   INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France
,
Jagadeesh Bayry
1   INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France
,
Anastas Pashov
1   INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France
,
Srini V. Kaveri
1   INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France
,
Roseline d’Oiron
2   Centre d’Hémophiles, Hôpital Bicêtre, Paris, France
,
Natalie Stieltjes
3   Centre des hémophiles, Hôpital Cochin, Paris, France
,
Valeri Roussel-Robert
3   Centre des hémophiles, Hôpital Cochin, Paris, France
,
Michel D. Kazatchkine
1   INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France
,
Olivier Boyer
4   Laboratoire de Biologie et Thérapeutique des pathologies immunitaires, CERVI, Hôpital Pitié-Salpêtrière, Paris, France
,
Sébastien Lacroix-Desmazes
1   INSERM U430 and Université Pierre et Marie Curie, Centre de Recherches Biomédicales des Cordeliers, Paris, France
› Institutsangaben
Financial support: This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), France, and by ZLB Bioplasma (Bern, Switzerland). NM is a recipient of a fellowship from the Agence Nationale de Recherches sur le Sida, France. JB is a recipient of a fellowship from the Ministère de la Recherche et de la Technologie, France. FVIII was a kind gift from Bayer Pharma (Puteaux, France).
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Publikationsverlauf

Received 19. Mai 2003

Accepted after revision 22. Juli 2003

Publikationsdatum:
05. Dezember 2017 (online)

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

 
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