Effect of clotting factors concentrates on lymphocyte and neutrophil function in vitro

Summary

Immunological abnormalities have been reported in haemophiliacs. Although infections with HIV, hepatitis and other viruses may contribute to these abnormalities, immune defects are detectable also in HIV seronegative haemophiliacs. It is likely that chronic exposure to extraneous proteins in clotting factor concentrates (CFCs) may play a role in immunomodulation, but the underlying mechanisms remain unclear. The results of the present paper show that: a) soluble HLA class I (sHLA-I), soluble Fas-ligand (sFas-L) and transforming growth factor beta 1 (TGF-β1) are detectable in plasma derived but not in recombinant CFCs; b) the level of sHLA-I and sFas-L is proportional to the grade of CFCs purity whereas TGF-β1 showed very variable levels; c) soluble molecules detected in CFCs exert immunomodulatory effects in vitro like apoptosis induction in Jurkat cells and inhibition of mixed lymphocyte reaction response, antigen-specific lymphocyte cytotoxic activity and neutrophil chemotaxis.

Keywords

Clotting factors concentrates - soluble HLA class I - soluble Fas ligand - transforming growth factor β1

• References

• 1 Vermont-Desrochers C, Rigal D, Blourde C, Bernaud J. Immunosuppressive property of a very high purity antihaemophilic preparation: a low molecular weight component inhibits an early step of PHA induced cell activation. Br J Haematol 1992; 80: 370-7.
• 2 Thorpe R, Dilger P, Dawson NJ, Barrowcliffe TW. Inhibition of interleukin-2 secretion by factor VIII concentrates: a possible cause of immunosuppression in haemophiliacs. Br J Haematol 1989; 71: 387-91.
• 3 Hodge G, Flower R, Han P. Effect of factor VIII concentrate on leukocyte cytokine production: characterization of TGF-beta as an immunomodulatory component on plasma-derived factor VIII concentrate. Br J Haematol 1999; 106: 784-91.
• 4 Hodge G, Han P. Effect of intermediate-purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor- is a significant immunomodulatory component of FVIII. Br J Haematol 2001; 115: 376-81.
• 5 Eibl MM, Ahmad R, Wolf HM, Linnau Y, Götz E, Mannhalter JW. A component of factor VIII preparations which can be separated from factor VIII activity down modulates human monocyte functions. Blood 1987; 69: 1153-60.
• 6 Hodge G, Lloyd JV, Hodge S, Story C, Han P. Functional lymphocyte immunophenotypes observed in thalassaemia and haemophilia patients receiving current blood product preparations. Br J Haematol 1999; 105: 817-25.
• 7 Hodge G, Han P. Effect of factor VIII concentrate on antigen-presenting cell (APC)/T-cell interactions in vitro: relevance to inhibitor for- mation and tolerance induction. Br J Haematol 2000; 109: 195-200.
• 8 Watson HG, Ludlam CA. Immunological abnormalities in haemophiliacs. Blood Rev 1992; 6: 26-33.
• 9 Fukushima Y, Makino M, Fukutake K, Okuyama K, Ueda M, Yorifugi H, Mimaya J, Fujimaki M, Komuro K. Immunological abnormalities in HIV-free haemophiliacs. J Clin Lab Immunol 1993; 40: 173-80.
• 10 Hoots K, Canty D. Clotting factor concentrates and immune function in haemophilic patients. Haemophilia 1998; 4: 704-13.
• 11 Barnstable CJ, Bodmer WF, Brown G, Galfre G, Milstein C, Williams AF, Ziegler AZ. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens: new tools for genetic analysis. Cell 1978; 14: 9-20.
• 12 Pellegrino MA, Ng AK, Russo C, Ferrone S. Heterogeneous distribution of determinants defined by monoclonal antibodies on HLA-A and B antigens bearing molecules. Transplantation 1982; 34: 18-23.
• 13 Böyum A. Separation of leukocytes from blood and bone marrow. Scand J Clin Lab Invest 1968; 21 (Suppl. 97) Suppl 77-89.
• 14 Ottonello L, Tortolina G, Amelotti M, Dallegri F. Soluble Fas Ligand is chemotactic for human neutrophilic polymorphonuclear leukocytes. J Immunol 1999; 162: 3601-6.
• 15 Russo C, Pellegrino MA, Ferrone S. A double-determinant immunoassay with monoclonal antibodies to the HLA-A, B, C complex. Transpl Proc 1983; 15: 66-7.
• 16 Gavioli R, Kurilla MG, de Campos-LimaPO, Wallace LE, Dolcetti R, Murray RJ, Rickinson AB, Masucci MG. Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4. J Virol 1993; 67: 1572-8.
• 17 Bass DA, Parce JW, Dechatelet LR, Szeida P, Seeds MC, Thomas M. Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol 1983; 130: 1910-7.
• 18 Martínez-Lorenzo MJ, Anel A, Gamen S, Monleón I, Lasierra P, Larrad L, Piñeiro A, Alava MA, Aval J. Activated human T cells release bioactive Fas ligand and APO2 ligand in microvescicles. J Immunol 1999; 163: 1274-81.
• 19 Hausmann R, Zavazava N, Steinmann J, Müller-Ruchholtz W. Interaction of papain-digested HLA class I molecules with human alloreactive cytotoxic T lymphocytes (CTL). Clin Exp Immunol 1993; 91: 183-8.
• 20 Zavazava N, Krönke M. Soluble HLA class I molecules induce apoptosis in alloreactive cytotoxic T lymphocytes. Nature Med 1996; 2: 1005-10.
• 21 Puppo F, Contini P, Ghio M, Brenci S, Scudeletti M, Filaci G, Ferrone S, Indiveri F. Soluble human MHC class I molecules induce soluble Fas ligand secretion and trigger apoptosis in activated CD8⁺ Fas(CD95)⁺ T lymphocytes. Int Immunol 2000; 12: 195-203.
• 22 Westhoff U, Grosse Wilde H. Soluble HLA class I and class II concentrations in factor VIII and PCC preparations. Vox Sang 1995; 68: 73-6.
• 23 Wadhwa M, Dilger P, Tubbs J, Mire-Sluis A, Barrowcliffe T, Thorpe R. 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.
• 24 Pearson HJL, Stirling D, Ludlam CA, Steel CM. TGF- is not the principal immunosuppressive component in coagulation factor concentrates. Br J Haematol 1999; 106: 971-9.
• 25 Wadhwa M, Barrowcliffe T, Thorpe R. Immunological effects of factor VIII concentrates: characterization of transforming growth factor as an immunomodulatory contaminant in factor VIII concentrates. Br J Haematol 2000; 109: 895-905.
• 26 Smid WM, Martens A, van der Meer J, Hegge-Paping CS, Halie MR. Soluble interleukin 2 receptor and soluble CD8 levels in previously treated human immunodeficiency-virus negative hemophiliacs multiply transfused with a monoclonal antibody-purified factor VIII concentrate. Transfusion 1997; 37: 86-9.
• 27 Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998; 101: 890-8.
• 28 McDonald PP, Fadok VA, Bratton D, Henson PM. Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-beta in macrophages that have ingested apoptotic cells. J Immunol 1999; 163: 6164-72.
• 29 Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998; 16: 137-61.
• 30 Chen WJ, Frank ME, Jin W, Wahl S. TFG- released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 2001; 14: 715-25.
• 31 Brandes ME, Mai UUE, Ohura K, Wahl SM. Type I transforming growth factor- receptors on neutrophils mediate chemotaxis to transforming growth factor-. J Immunol 1991; 147: 1600-6.
• 32 Haines KA, Kolasinski SL, Cronstein BN, Reibman J, Gold LI, Weissmann G. Chemo-attraction of neutrophils by substance P and transforming growth factor- 1 is inadequately explained by current models of lipid remodelling. J Immunol 1993; 151: 1491-9.
• 33 Lehrer RI, Ganz T, Selsted ME, Babior BM, Curnutte JT. Neutrophils and host defense. Ann Intern Med 1988; 109: 127-42.
• 34 Serlenga E, Ventura MT, Polignano AV, Tor-torella C, Antinaci S, Bonomo L. Serum suppressive factors may account for the reduced polymorphonuclear cell function in haemophilia. Rec Prog Med 1990; 81: 792-6.
• 35 Dzik S, Blajchman MA, Blumberg N, Kirkley SA, Heal JM, Wood K. Current research on the immunomodulatory effect of allogeneic blood transfusion. Vox Sang 1996; 70: 187-94.
• 36 van de WateringLMG, Hermans J, Houbiers JG, van den BroekPJ, Bouter H, Boer F, Harvey MS, Huysmans HA, Brand A. Beneficial effects of leukocyte depletion of transfused blood on postoperative complications in paients undergoing cardiac surgery. A randomized clinical trial. Circulation 1998; 97: 562-8.
• 37 Berntorp E. Immune tolerance induction: recombinant vs. human-derived product. Haemophilia 2001; 7: 109-13.