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; Yoshihiko Sakurai; Takeshi Yoshioka; Yuji Tsuruta; Ryuji Suzuki; Midori Shima; Akira Yoshioka

doi:10.1160/TH02-12-0302

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan

,

Yoshihiko Sakurai

²Department of Pediatrics, Nara Medical University, Kashihara, Japan

,

Takeshi Yoshioka

¹Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan

,

Yuji Tsuruta

¹Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan

,

Ryuji Suzuki

¹Department of Medical Science, Discovery Research Laboratories, Shionogi Research Laboratories, Shionogi and Co. Ltd., Osaka, Japan

,

Midori Shima

²Department of Pediatrics, Nara Medical University, Kashihara, Japan

,

Akira Yoshioka

²Department of Pediatrics, Nara Medical University, Kashihara, Japan

› Institutsangaben

Abstract

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

Volltext

Referenzen

References
1 Hoyer LW. Hemophilia A. N Engl J Med 1994; 330: 38-47.
2 Watson HG, Ludlam CA. Immunological abnormalities in haemophiliacs. Blood Rev 1992; 6: 26-33.
3 Hoots K, Canty D. Clotting factor concentrates and immune function in haemophilic patients. Haemophilia 1998; 4: 704-13.
4 Gomperts ED, de Biasi R, De Vreker R. The impact of clotting factor concentrates on the immune system in individuals with hemophilia. Transfus Med Rev 1992; 6: 44-54.
5 Matheson DS, Green BJ, Fritzler MJ. et al. Humoral immune response in patients with hemophilia. Clin Immunol Immunopathol 1987; 44: 41-50.
6 Berntorp E. Impact of replacement therapy on the evolution of HIV infection in hemophiliacs. Thromb Haemost 1994; 71: 678-83.
7 Mannhalter JW, Ahmad R, Leibl H. et al. Comparable modulation of human monocyte functions by commercial factor VIII concentrates of varying purity. Blood 1988; 71: 1662-8.
8 Pasi KJ, Hill FG. In vitro and in vivo inhibition of monocyte phagocytic function by factor VIII concentrates: correlation with concentrate purity. Br J Haematol 1990; 76: 88-93.
9 Schulman S. Effects of factor VIII concentrates on the immune system in hemophilic patients. Ann Hematol 1991; 63: 145-51.
10 Hodge G, Lloyd JV, Hodge S. et al. Functional lymphocyte immunophenotypes observed in thalassaemia and haemophilia patients receiving current blood product preparations. Br J Haematol 1999; 105: 817-25.
11 Meijer K, Van Der Meer J, Smit JW. et al. Lymphocyte subset abnormalities in multi-transfused HIV-negative haemophilia A patients are not due to chronic hepatitis C virus infection. Br J Haematol 2000; 109: 529-33.
12 Roy G, Pardo A, Leyva-Cobian F. Phenotypic and functional abnormalities in monocytes from patients with haemophilia A treated with factor VIII concentrates. Acta Haematol 1988; 79: 26-32.
13 Madhok R, Gracie JA, Smith J. et al. Capacity to produce interleukin 2 is impaired in haemophilia in the absence and presence of HIV 1 infection. Br J Haematol 1990; 76: 70-4.
14 Allersma DP, Smid WM, van der Does JA. et al. Effects of chronic factor VIII substitution on immune parameters in HIV seronegative haemophiliacs: a comparison between cryo-precipitate and factor VIII concentrate. Thromb Haemost 1996; 75: 261-6.
15 Wadhwa M, Dilger P, Tubbs J. et al. Mechanisms of inhibition of T cell IL-2 secretion by factor VIII concentrates. Br J Haematol 1992; 82: 575-83.
16 Hodge G, Han P. Effect of intermediate-purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor-beta is a significant immunomodulatory component of FVIII. Br J Haematol 2001; 115: 376-81.
17 Matsutani T, Yoshioka T, Tsuruta Y. et al. Analysis of TCRAV and TCRBV repertoires in healthy individuals by microplate hybridization assay. Hum Immunol 1997; 56: 57-69.
18 Matsutani T, Yoshioka T, Tsuruta Y. et al. Restricted usage of T-cell receptor alpha-chain variable region (TCRAV) and T-cell receptor beta-chain variable region (TCRBV) repertoires after human allogeneic haematopoietic transplantation. Br J Haematol 2000; 109: 759-69.
19 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
20 Hollander M, Wolfe DA. Nonparametric Statistical Methods Chap.4. John Wiley & Sons 1973; 67-74.
21 Cuthbert RJ, Ludlam CA, Steel CM. et al. Immunological studies in HIV seronegative haemophiliacs: relationships to blood product therapy. Br J Haematol 1992; 80: 364-9.
22 Anh-Tuan N, Novak E. Hepatitis B surface antigen circulating immune complexes (HBsAg-CICs) in patients with hepatitis B and asymptomatic HBsAg carriers. Clin Exp Immunol 1981; 43: 246-53.
23 Gomperts ED. Clotting factors isolated with monoclonal antibodies. Curr Stud Hematol Blood Transfus 1991; 58: 52-8.
24 Fukushima Y, Makino M, Fukutake K. et al. Immunological abnormalities in HIV-free haemophiliacs. J Clin Lab Immunol 1993; 40: 173-80.
25 Uemura K, Yoshizawa M, Ota M. et al. Analysis of T cell repertoire in the liver of patients with chronic hepatitis C. Clin Exp Immunol 2000; 121: 120-6.
26 Thorpe R, Dilger P, Dawson NJ. et al. Inhibition of interleukin-2 secretion by factor VIII concentrates: a possible cause of immunosuppression in haemophiliacs. Br J Haematol 1989; 71: 387-91.
27 Wadhwa M, Dilger P, Tubbs J. et al. Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs. Blood 1994; 84: 2021-30.
28 Lederman MM, Saunders C, Toossi Z. et al. Antihemophilic factor [factor VIII] preparations inhibit lymphocyte proliferation and production of interleukin-2. J Lab Clin Med 1986; 107: 471-8.
29 Hamann D, Baars PA, Rep MH. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997; 186: 1407-18.
30 Azuma M, Phillips JH, Lanier LL. CD28- T lymphocytes. Antigenic and functional properties. J Immunol 1993; 150: 1147-59.
31 Monteiro J, Batliwalla F, Ostrer H. et al. Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol 1996; 156: 3587-90.
32 Fagnoni FF, Vescovini R, Mazzola M. et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 1996; 88: 501-7.
33 Vallejo AN, Brandes JC, Weyand CM. et al. Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol 1999; 162: 6572-9.
34 Wang EC, Moss PA, Frodsham P. et al. CD8-highCD57+ T lymphocytes in normal, healthy individuals are oligoclonal and respond to human cytomegalovirus. J Immunol 1995; 155: 5046-56.
35 Weekes MP, Wills MR, Mynard K. et al. Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+CD28- CD8+ T-cell population. Immunology 1999; 98: 443-9.
36 Weekes MP, Carmichael AJ, Wills MR. et al. Human CD28-CD8+ T cells contain greatly expanded functional virus-specific memory CTL clones. J Immunol 1999; 162: 7569-77.
37 Lewis DE, Yang L, Luo W. et al. HIV-specific cytotoxic T lymphocyte precursors exist in a CD28-CD8+ T cell subset and increase with loss of CD4 T cells. AIDS 1999; 13: 1029-33.
38 Dalod M, Sinet M, Deschemin JC. et al. Altered ex vivo balance between CD28+ and CD28- cells within HIV-specific CD8+ T cells of HIV-seropositive patients. Eur J Immunol 1999; 29: 38-44.