Understanding loss of donor white blood cell immunogenicity after pathogen reduction: mechanisms of action in ultraviolet illumination and riboflavin treatment.
BACKGROUND
Donor white blood cells (WBCs) present in transfusion products can lead to immune sequelae such as production of HLA antibodies or graft-versus-host disease in susceptible transfusion recipients. Eliminating the immunogenicity of blood products may prove to be of clinical benefit, particularly in patients requiring multiple transfusions in whom allosensitization is common. This study examines a method of pathogen reduction based on ultraviolet light illumination in the presence of riboflavin. In addition to pathogens, WBCs treated with this system are affected and fail to stimulate proliferation of allogeneic peripheral blood mononuclear cells (PBMNCs) in vitro.


METHODS
This study sought to determine the mechanisms regulating this loss of immunogenicity. Treated cells were examined for surface expression of a number of molecules involved in activation and adhesion, viability, cell-cell conjugation, and ability to stimulate immune responses in allogeneic PBMNCs.


RESULTS
Compared with untreated controls, ultraviolet (UV)-irradiated antigen-presenting cells showed slightly reduced surface expression of HLA Class II and costimulatory molecules and had more significant reductions in surface expression of a number of adhesion molecules. Furthermore, treated cells had a severe defect in cell-cell conjugation. The observed loss of immunogenicity was nearly complete, with UV-irradiated cells stimulating barely measurable interferon-gamma production and no detectable STAT-3, STAT-5, or CD3-epsilon phosphorylation in allospecific primed T cells.


CONCLUSIONS
These results suggest that defective cell-cell adhesion prevents UV-irradiated cells from inducing T-cell activation.
Jackman
Rachael P
RP
Department of Laboratory Medicine and Medicine, Blood Systems Research Institute, University of California, San Francisco, California, USA. rjackman@bloodsystems.org
Heitman
John W
JW
Marschner
Susanne
S
Goodrich
Raymond P
RP
Norris
Philip J
PJ
D001793:Blood Preservation / Q000379:methods*; D001803:Blood Transfusion; D017848:Blood-Borne Pathogens / Q000528:radiation effects; D015815:Cell Adhesion Molecules / Q000276:immunology; D016923:Cell Death / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000528:radiation effects; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D008213:Lymphocyte Activation; D017319:Photosensitizing Agents / Q000494:pharmacology*; D012256:Riboflavin / Q000494:pharmacology*; D014466:Ultraviolet Rays
D015815:Cell Adhesion Molecules; D006680:HLA Antigens; D007519:Isoantigens; D017319:Photosensitizing Agents; D012256:Riboflavin
Anesthesiology. 1993 Dec;79(6):1419-21
8267214
Photochem Photobiol. 2005 Mar-Apr;81(2):474-80
15623353
Biol Pharm Bull. 1994 Aug;17(8):1065-9
7820109
Int Arch Allergy Appl Immunol. 1971;41(5):670-8
4273315
Exp Hematol. 1990 Sep;18(8):916-9
2387342
J Invest Dermatol. 1992 Jun;98(6):923-8
1350607
Blood. 1996 Mar 15;87(6):2386-93
8630402
Semin Hematol. 2007 Jan;44(1):24-31
17198844
Photochem Photobiol. 1997 Apr;65(4):609-15
9114735
N Engl J Med. 1997 Dec 25;337(26):1861-9
9417523
J Invest Dermatol. 1994 Apr;102(4):422-7
8151120
Semin Immunopathol. 2007 Apr;29(1):65-70
17621955
Langmuir. 2004 Aug 31;20(18):7729-35
15323525
Transfusion. 2007 Feb;47(2):240-7
17302769
Int J Radiat Biol. 2002 Jul;78(7):577-83
12079536
Blood. 1998 Mar 15;91(6):2180-8
9490707
Int J Dermatol. 2001 Feb;40(2):89-100
11328388
Am J Hematol. 2008 Jul;83(7):589-91
18335565
Clin Exp Immunol. 1987 Oct;70(1):116-26
2961488
Cell Immunol. 1983 Aug;80(1):151-62
6603274
Blood. 1994 Mar 15;83(6):1683-9
8123860
Transfusion. 2005 Jun;45(6):920-6
15934990
Transfusion. 2007 Aug;47(8):1455-67
17655590
Transfusion. 2000 Mar;40(3):348-52
10738038
Vox Sang. 1993;65(1):25-31
8362512
Immunol Today. 1990 Jun;11(6):211-6
2162180
Transfusion. 1996 Apr;36(4):296-302
8623127
Blood Cells Mol Dis. 2002 Jul-Aug;29(1):24-34
12482400
Blood Rev. 2001 Jun;15(2):103-8
11409910
Cell. 1992 Dec 24;71(7):1081-91
1473146
J Cutan Pathol. 1997 May;24(5):278-85
9194580
Mutat Res. 2005 Apr 1;571(1-2):185-205
15748647
Transfus Apher Sci. 2006 Aug;35(1):5-17
16935562
Mol Cell Biol. 1991 May;11(5):2804-11
1901948
Transfus Med Rev. 1990 Oct;4(4 Suppl 1):19-23
2134637
Springer Semin Immunopathol. 1992;13(3-4):333-44
1357761
Transfusion. 2001 May;41(5):637-42
11346700
Photochem Photobiol. 2004 Jul-Aug;80:15-21
15339215
Clin Exp Immunol. 1996 Aug;105(2):389-96
8706350
Science. 1993 Sep 10;261(5127):1442-5
8367725
Blood. 2005 May 15;105(10):4106-14
15692069
J Clin Invest. 1990 May;85(5):1529-36
1970582
Blood. 1999 May 1;93(9):3140-7
10216113
Langmuir. 2009 Jan 6;25(1):345-51
19067577
Transfusion. 1992 Feb;32(2):169-72
1542924
Vox Sang. 2006 Feb;90(2):85-91
16430665
Blood. 1993 Jun 1;81(11):2987-97
8098966
Transfusion. 2006 Apr;46(4):642-8
16584442
Transfus Apher Sci. 2007 Oct;37(2):131-7
17950672
Vox Sang. 2000;78 Suppl 2:197-201
10938952
Science. 1999 Jul 9;285(5425):221-7
10398592
Int J Cancer. 1998 Sep 25;78(1):70-5
9724096