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Thromb Haemost 2000; 84(04): 643-652
DOI: 10.1055/s-0037-1614081
Review Article
Schattauer GmbH

Sensitization of CD4+ T Cells to Coagulation Factor VIII: Response in Congenital and Acquired Hemophilia Patients and in Healthy Subjects

Mark T. Reding
1   From The Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, USA
2   Department of Medicine, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
Huiyun Wu
1   From The Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
Mark Krampf
1   From The Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
David K. Okita
1   From The Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
Brenda M. Diethelm-Okita
1   From The Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
Beverly A. Christie
2   Department of Medicine, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
Nigel S. Key
2   Department of Medicine, University of Minnesota, Minneapolis-St. Paul, MN, USA
,
Bianca M. Conti-Fine   4
1   From The Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St. Paul, MN, USA
3   Department of Pharmacology, University of Minnesota, Minneapolis-St. Paul, MN, USA
› Author AffiliationsSupported by the NHLBI grant HL61922 (to B. M. C.-F.) and a research grant from the Hemophilia Association of New York (to N.K. and B. M. C.-F.). M. T. R. is the recipient of a Judith Graham Pool Postdoctoral Research Fellowship from the National Hemophilia Foundation.
We are grateful to Dr. Sanford Weisberg, Director of the Statistical Consulting Services of the School of Statistics of the University of Minnesota, for his precious help in analyzing our data, and to Dr. Jiahua Qian for her excellent suggestions and productive discussions.
Further Information

Publication History

Received 14 January 2000

Accepted after resubmission 01 June 2000

Publication Date:
11 December 2017 (online)

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Summary

Antibodies (Ab) that inhibit factor VIII (fVIII) may develop in patients with hemophilia A and rarely in individuals without congenital fVIII deficiency (acquired hemophilia). Synthesis of fVIII inhibitors requires CD4+ T cells. We investigated the proliferative response of blood CD4+ cells from 11 patients with congenital or acquired hemophilia and 12 healthy subjects, to recombinant human fVIII, and to pools of overlapping synthetic peptides spanning the sequences of individual fVIII domains. All patients had CD4+ cells that responded to fVIII. The intensity of the responses fluctuated over time: several patients had brief periods when they did not respond to fVIII. All healthy subjects had transient CD4+ responses to fVIII, that were significantly lower than those of hemophilia patients. Also, healthy subjects responded to fVIII less frequently and for shorter periods than hemophilia patients. All patients and healthy subjects recognized several fVIII domains: the A3 domain was recognized most strongly and frequently. The transient sensitization of CD4+ cells to fVIII in healthy subjects suggests that inadequate tolerization of CD4+ cells to fVIII, due to lack of endogenous fVIII, is an important factor in the development of clinically significant anti-fVIII antibodies in hemophilia A.

Key words

Immune response - T cells - factor VIII - inhibitors

4 Previously known as Bianca M. Conti-Tronconi


 

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