Adenovirus-Antibody Complexes Contributed to Lethal Systemic Inflammation in a Gene Therapy Trial.
Adenoviridae
/ genetics
Adenoviruses, Human
/ immunology
Animals
Antibodies, Viral
/ immunology
Antigen-Antibody Complex
/ immunology
Clinical Trials as Topic
Dendritic Cells
/ immunology
Disease Models, Animal
Genetic Therapy
/ adverse effects
Genetic Vectors
/ adverse effects
Humans
Inflammation
/ etiology
Mice
Transduction, Genetic
OTCD
adenovirus
antibody mediated enhancement
cytokine
dendritic cell
gene therapy
gene therapy trial
innate immune response
lethal systemic inflammatory response
ornithine transcarbamylase deficiency
safety
transduction/activation
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
04 03 2020
04 03 2020
Historique:
received:
09
10
2019
revised:
06
01
2020
accepted:
06
01
2020
pubmed:
9
2
2020
medline:
29
12
2020
entrez:
9
2
2020
Statut:
ppublish
Résumé
Intra-arterial administration of an adenovirus serotype 5 (Ad5) vector in a gene therapy trial caused lethal, systemic inflammation in subject 019 with ornithine transcarbamylase deficiency. This unanticipated inflammatory response was absent in another subject receiving the same vector dose and in 16 subjects receiving lower vector doses. We hypothesized that an immune memory to a previous natural adenovirus infection enhanced the immune response to high-dose systemic Ad5 vector, causing the exaggerated immune response in subject 019. To investigate this, we found that rabbit polyclonal sera to Ad5 and pooled human immunoglobulin (Ig) inhibited Ad5 vector transduction of non-immune cells in vitro, but enhanced transduction and activation of human dendritic cells (DCs). Sera from approximately 7% of normal human subjects and 50% of patients treated topically with Ad5 vectors enhanced Ad5 transduction and activation of DCs, apparently from formation of Ig-Ad5 immune complexes and binding to DCs through FcγR. Subject 019's blood substantially increased Ad5-vector activation of human DC primary cultures at levels exceeding those from normal subjects. Although this study is based on one event in a single subject, the results implicate a pre-existing humoral immune response to Ad5 in the lethal systemic inflammatory response that occurred in subject 019.
Identifiants
pubmed: 32035027
pii: S1525-0016(20)30030-7
doi: 10.1016/j.ymthe.2020.01.006
pmc: PMC7054813
pii:
doi:
Substances chimiques
Antibodies, Viral
0
Antigen-Antibody Complex
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
784-793Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL059407
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK047757
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020. Published by Elsevier Inc.
Références
Virology. 1992 Jun;188(2):793-800
pubmed: 1585648
Mol Ther. 2006 Jul;14(1):118-28
pubmed: 16580883
Virology. 1996 May 1;219(1):220-7
pubmed: 8623532
Mol Genet Metab. 2003 Sep-Oct;80(1-2):148-58
pubmed: 14567964
J Virol. 2002 Jun;76(11):5711-9
pubmed: 11991999
Nat Rev Immunol. 2014 Feb;14(2):94-108
pubmed: 24445665
Hum Gene Ther. 2018 Mar;29(3):285-298
pubmed: 29378426
Gene Ther. 1999 Sep;6(9):1574-83
pubmed: 10490767
Mol Ther. 2001 May;3(5 Pt 1):708-22
pubmed: 11356076
Mol Ther. 2009 Oct;17(10):1822-9
pubmed: 19638959
Gene Ther. 2005 Mar;12(5):427-36
pubmed: 15647774
Hematol Oncol Clin North Am. 2017 Oct;31(5):771-785
pubmed: 28895846
Virus Genes. 2017 Oct;53(5):692-699
pubmed: 28755290
J Immunother Cancer. 2019 Jan 28;7(1):20
pubmed: 30691536
J Gene Med. 2007 Dec;9(12):1033-45
pubmed: 17966114
Immunol Rev. 2015 Nov;268(1):340-64
pubmed: 26497532
Vaccine. 2019 Aug 14;37(35):4848-4849
pubmed: 30424888
Mol Ther. 2001 May;3(5 Pt 1):697-707
pubmed: 11356075
Genome Res. 2000 Nov;10(11):1719-25
pubmed: 11076857
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407-11
pubmed: 8183921
Hum Gene Ther. 2009 Apr;20(4):293-301
pubmed: 19272012
Somat Cell Mol Genet. 1993 Sep;19(5):449-58
pubmed: 8291022
J Exp Med. 2008 Nov 24;205(12):2717-25
pubmed: 18981239
Mol Ther. 2018 Mar 7;26(3):664-668
pubmed: 29428298
Hum Gene Ther. 2004 May;15(5):519-30
pubmed: 15144581