title: Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy.
abstract: The transfer of T cell receptor (TCR) genes can be used to induce immune reactivity toward defined antigens to which endogenous T cells are insufficiently reactive. This approach, which is called TCR gene therapy, is being developed to target tumors and pathogens, and its clinical testing has commenced in patients with cancer. In this study we show that lethal cytokine-driven autoimmune pathology can occur in mouse models of TCR gene therapy under conditions that closely mimic the clinical setting. We show that the pairing of introduced and endogenous TCR chains in TCR gene-modified T cells leads to the formation of self-reactive TCRs that are responsible for the observed autoimmunity. Furthermore, we demonstrate that adjustments in the design of gene therapy vectors and target T cell populations can be used to reduce the risk of TCR gene therapy-induced autoimmune pathology.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. g.bendle@nki.nl
authors.forename: Gavin M
authors.initials: GM
authors.lastname: Bendle
authors.forename: Carsten
authors.initials: C
authors.lastname: Linnemann
authors.forename: Anna I
authors.initials: AI
authors.lastname: Hooijkaas
authors.forename: Laura
authors.initials: L
authors.lastname: Bies
authors.forename: Moniek A
authors.initials: MA
authors.lastname: de Witte
authors.forename: Annelies
authors.initials: A
authors.lastname: Jorritsma
authors.forename: Andrew D M
authors.initials: AD
authors.lastname: Kaiser
authors.forename: Nadine
authors.initials: N
authors.lastname: Pouw
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.forename: Elisa
authors.initials: E
authors.lastname: Kieback
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
mesh_terms: D000818:Animals; D019672:Genes, T-Cell Receptor; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell
references.citation: J Clin Oncol. 1991 Oct;9(10):1889-902
references.pmid: 1919639
references.citation: Cancer Cell. 2005 Nov;8(5):369-80
references.pmid: 16286245
references.citation: Cancer Res. 2007 Apr 15;67(8):3898-903
references.pmid: 17440104
references.citation: J Immunol. 2008 Aug 15;181(4):2563-71
references.pmid: 18684947
references.citation: J Immunol. 2005 Nov 15;175(10):7046-52
references.pmid: 16272366
references.citation: Blood. 2009 Jul 16;114(3):535-46
references.pmid: 19451549
references.citation: Nat Immunol. 2001 Oct;2(10):957-61
references.pmid: 11577349
references.citation: Blood. 2006 Aug 1;108(3):870-7
references.pmid: 16861342
references.citation: J Exp Med. 2003 Aug 18;198(4):569-80
references.pmid: 12925674
references.citation: Science. 2006 Oct 6;314(5796):126-9
references.pmid: 16946036
references.citation: Nat Med. 2001 Oct;7(10):1118-22
references.pmid: 11590434
references.citation: Nat Med. 2008 Dec;14(12):1390-5
references.pmid: 18997777
references.citation: Proc Natl Acad Sci U S A. 2005 May 31;102(22):7934-9
references.pmid: 15908507
references.citation: Cancer Immunol Immunother. 2009 May;58(5):809-22
references.pmid: 19189103
references.citation: J Clin Invest. 2005 Jun;115(6):1616-26
references.pmid: 15931392
references.citation: Transfusion. 2007 Aug;47(8):1405-11
references.pmid: 17655584
references.citation: Blood. 2007 Nov 15;110(10):3564-72
references.pmid: 17660381
references.citation: Br J Haematol. 2002 May;117(2):275-87
references.pmid: 11972509
references.citation: J Exp Med. 1997 Mar 3;185(5):833-41
references.pmid: 9120389
references.citation: Blood. 2009 Jan 29;113(5):1006-15
references.pmid: 18978209
references.citation: J Immunol. 2007 Oct 15;179(8):5534-42
references.pmid: 17911640
references.citation: Gene Ther. 2000 Aug;7(16):1369-77
references.pmid: 10981663
references.citation: Nat Rev Immunol. 2006 May;6(5):383-93
references.pmid: 16622476
references.citation: Cancer Res. 2006 Sep 1;66(17):8878-86
references.pmid: 16951205
references.citation: Blood. 2007 Mar 15;109(6):2331-8
references.pmid: 17082316
references.citation: J Immunol. 2008 Oct 1;181(7):5128-36
references.pmid: 18802117
references.citation: J Immunol. 1998 Nov 15;161(10):5133-7
references.pmid: 9820481
references.citation: Blood. 2010 Jan 21;115(3):541-8
references.pmid: 19903901
references.citation: J Exp Med. 2004 Apr 5;199(7):885-94
references.pmid: 15051765
references.citation: Nature. 2001 May 17;411(6835):380-4
references.pmid: 11357146
references.citation: Cancer Res. 2000 Dec 15;60(24):6995-7001
references.pmid: 11156402
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):623-8
references.pmid: 18182487
references.citation: J Immunol. 2002 Aug 15;169(4):1753-9
references.pmid: 12165496
references.citation: J Immunother. 2002 Sep-Oct;25(5):385-95
references.pmid: 12218776
references.citation: J Immunol. 2006 Jul 15;177(2):976-82
references.pmid: 16818753
references.citation: J Immunol. 2008 Jun 1;180(11):7736-46
references.pmid: 18490778
references.citation: Curr Opin Immunol. 2009 Apr;21(2):209-14
references.pmid: 19321326
references.citation: Nat Rev Immunol. 2002 Jul;2(7):512-9
references.pmid: 12094225
references.citation: Exp Hematol. 2004 Dec;32(12):1163-72
references.pmid: 15588941
references.citation: J Immunol. 2007 Nov 1;179(9):5803-10
references.pmid: 17947653
references.citation: J Immunol. 2008 Jan 1;180(1):391-401
references.pmid: 18097040