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Thromb Haemost 2003; 90(02): 279-292
DOI: 10.1160/TH02-12-0302
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Replacement therapy with plasma-derived factor VIII concentrates induces skew in T-cell receptor usage and clonal expansion of CD8+ T-cell in HIV-seronegative hemophilia patients

Takaji Matsutani
1   Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan
,
Yoshihiko Sakurai
2   Department of Pediatrics, Nara Medical University, Kashihara, Japan
,
Takeshi Yoshioka
1   Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan
,
Yuji Tsuruta
1   Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan
,
Ryuji Suzuki
1   Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan
,
Midori Shima
2   Department of Pediatrics, Nara Medical University, Kashihara, Japan
,
Akira Yoshioka
2   Department of Pediatrics, Nara Medical University, Kashihara, Japan
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Publikationsverlauf

Received 05. Dezember 2002

Accepted after revision 20. April 2003

Publikationsdatum:
06. Dezember 2017 (online)

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Summary

Replacement therapy with factor VIII (FVIII) products causes immune abnormalities in human immunodeficiency virus (HIV)-seronegative hemophilia patients. However, the question remains why an absolute increase in the number of CD8+ T-cells and diminished proliferation responses of lymphocytes to antigen stimulation in vitro occurs in HIV-seronegative hemophilia patients.

To examine whether the FVIII products induce skewing of T-cell receptor (TCR) repertoires, TCR variable region α-chain and β–chain repertoires were analyzed for peripheral blood mononuclear cells (PBMCs) from 15 hemophilia patients treated with heated and/or non-heated plasma-derived FVIII concentrates and 10 age-matched healthy adults. Also, T-cell clonality was compared between these groups using complementarity-determining region 3 (CDR3) size spectratyping. The skewing of TCR repertoires was significantly greater for hemophilia patients than healthy controls. The extent of T-cell clonality was greater for hemophilia patients than the controls, indicating that clonal T-cells frequently expanded in hemophilia patients. The skew in TCR usage and clonal expansion were primarily observed in patients treated with non-heated plasma-derived products.

The spectratyping and sequencing of CDR3 regions revealed that the clonal expansion of T-cells was observed for CD8+ T-cells, but not CD4+ T-cells.

These results suggest that extensive expansion of CD8+ T-cells is induced by some viruses other than HIV present in FVIII preparations, and the resulting accumulation of CD8+ T-cells is responsible for changes in peripheral T-cell population in HIV-seronegative hemophilia patients.

Keywords

Hemophilia - T lymphocytes - T cell receptors - clonal expansion
 

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