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Thromb Haemost 1996; 76(01): 017-022
DOI: 10.1055/s-0038-1650515
Original Article
Schattauer GmbH Stuttgart

T Lymphocyte Proliferative Responses Induced by Recombinant Factor VIII in Hemophilia A Patients with Inhibitors

Sylvia T Singer
1   The Hematology-Oncology Department, Children’s Hospital Oakland, Oakland, CA, USA
,
Joseph E Addiego Jr
1   The Hematology-Oncology Department, Children’s Hospital Oakland, Oakland, CA, USA
,
Donald C Reason
2   The Children’s Hospital Oakland Research Institute, Oakland, CA, USA
,
Alexander H Lucas
2   The Children’s Hospital Oakland Research Institute, Oakland, CA, USA
› Author Affiliations
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Publication History

Received: 06 November 1995

Accepted after resubmission09 April 1996

Publication Date:
26 July 2018 (online)

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Summary

In this study we sought to determine whether factor VUI-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 µg of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production