Summary

In the present study, we have analyzed the T cell receptor(TCR) repertoires of CD4+ T cells isolated from peripheralblood of 10 inhibitor-positive patients with severe hemophiliaA. The distribution of complementarity determining region(CDR3) lengths of the beta chain of the TCRs was analyzed byspectratyping prior to and following in vitro stimulation of thecells with human factor VIII (FVIII). The repertoires of CD4+ Tcells of patients were perturbed when compared to those ofhealthy blood donors. The perturbations of T cell repertoireswere heterogeneous among patients with respect to the numberand the nature of V-beta (BV) families that exhibited expansionfollowing incubation with FVIII. Some patients showedalterations in one or two BV families, others exhibited moreperturbed repertoires affecting 5 to 8 of the 14 BV familiestested. Alterations of BV2, BV5 and/or BV9 were consistentlyfound after incubation of CD4+ T cells in the presence of FVIIIin 80% of the patients.These findings indicate that the presenceof FVIII inhibitors in patients with severe hemophilia A is associatedwith measurable perturbations of the CD4+ T cell rep-ertoirethat results from oligoclonal expansion of FVIII-specificcells and may be relevant for the design of strategies aimed atmodulating the anti-FVIII immune responses by T cell-targetedtherapy