Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology.
Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p< 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p< 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom; sjwhitfield@dstl.gov.uk.
Sarah J C
SJC
Whitfield
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
Chris
C
Taylor
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.|Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
Jane E
0000-0002-7915-0196
JE
Risdall
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
Gareth D
GD
Griffiths
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
James T A
JTA
Jones
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
E Diane
ED
Williamson
Division of Bacteriology, National Institute for Biological Standards and Control, Potters Bar EN6 3QG, United Kingdom.
Sjoerd
S
Rijpkema
Division of Biotherapeutics, National Institute for Biological Standards and Control, Potters Bar EN6 3QG, United Kingdom; and.
Luisa
0000-0001-5642-5559
L
Saraiva
Division of Biotherapeutics, National Institute for Biological Standards and Control, Potters Bar EN6 3QG, United Kingdom; and.
Sandrine
0000-0002-9697-1834
S
Vessillier
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
A Christopher
AC
Green
Department of Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire SP4 0JQ, United Kingdom.|Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Alun J
AJ
Carter
D000069594:Abatacept / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001835:Body Weight; D016207:Cytokines / Q000276:immunology; D004768:Enterotoxins / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D008168:Lung / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000276:immunology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D004768:Enterotoxins; D007376:Interleukin-2; D015850:Interleukin-6; C577686:interleukin-6, mouse; C031818:enterotoxin B, staphylococcal; D000069594:Abatacept; D007371:Interferon-gamma