title: Emergent autoimmunity in graft-versus-host disease.
abstract: Donor T-cell recognition of host alloantigens presented by host antigen-presenting cells (APCs) is necessary for the induction of graft-versus-host disease (GVHD), but whether direct alloreactivity is sufficient for the propagation of GVHD is unknown. In this study, we demonstrate that GVHD cannot be effectively propagated through the direct pathway of allorecognition. Rather, donor T-cell recognition of antigens through the indirect pathway is necessary for the perpetuation of GVHD. Furthermore, GVHD results in the breaking of self tolerance, resulting in the emergence of donor T cells that can cause autoimmune disease in syngeneic recipients. Notably, GVHD-induced autoreactivity is donor APC dependent, transferable into secondary hosts, and involves cells of the innate immune system. These results indicate that donor T-cell--mediated pathologic damage during GVHD becomes donor APC dependent and provide a mechanistic explanation for the long-standing observation that GVHD is associated with autoimmune clinical manifestations.
authors.affiliation: Bone Marrow Transplant Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tivol
authors.forename: Richard
authors.initials: R
authors.lastname: Komorowski
authors.forename: William R
authors.initials: WR
authors.lastname: Drobyski
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity; D016026:Bone Marrow Transplantation / Q000379:methods*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D046528:Chimerism; D003092:Colitis / Q000276:immunology; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000628:therapy*; D006098:Granulocytes / Q000276:immunology; D007107:Immune System; D007108:Immune Tolerance; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
references.citation: J Exp Med. 1993 Jul 1;178(1):237-44
references.pmid: 8100269
references.citation: J Exp Med. 1992 Jan 1;175(1):305-8
references.pmid: 1730925
references.citation: Cell. 1993 Oct 22;75(2):253-61
references.pmid: 8402910
references.citation: Curr Opin Immunol. 1993 Oct;5(5):800-3
references.pmid: 8240743
references.citation: Int Immunol. 1993 Nov;5(11):1461-71
references.pmid: 7903159
references.citation: J Exp Med. 1994 Feb 1;179(2):589-600
references.pmid: 7905019
references.citation: J Immunol. 1994 Feb 15;152(4):1609-17
references.pmid: 7907102
references.citation: J Immunol. 1994 Apr 1;152(7):3685-92
references.pmid: 8144943
references.citation: Bone Marrow Transplant. 1994 Oct;14(4):525-33
references.pmid: 7858527
references.citation: Science. 1995 Jun 9;268(5216):1472-6
references.pmid: 7770771
references.citation: Nature. 1998 Mar 5;392(6671):86-9
references.pmid: 9510252
references.citation: J Immunol. 1997 Dec 1;159(11):5391-9
references.pmid: 9548479
references.citation: Transplantation. 2000 Feb 15;69(3):446-9
references.pmid: 10706060
references.citation: Blood. 2000 Jun 15;95(12):3832-9
references.pmid: 10845917
references.citation: Blood. 2002 Feb 15;99(4):1442-8
references.pmid: 11830498
references.citation: Annu Rev Immunol. 2002;20:495-549
references.pmid: 11861611
references.citation: J Immunol. 2002 Aug 1;169(3):1626-33
references.pmid: 12133993
references.citation: J Immunol. 2002 Dec 15;169(12):7111-8
references.pmid: 12471148
references.citation: Transplantation. 2003 Jan 27;75(2):221-5
references.pmid: 12548127
references.citation: Blood. 2003 Jul 15;102(2):429-35
references.pmid: 12663438
references.citation: Hematol Oncol. 2003 Dec;21(4):149-61
references.pmid: 14735553
references.citation: J Exp Med. 2004 Feb 2;199(3):323-35
references.pmid: 14744995
references.citation: J Exp Med. 2004 May 3;199(9):1285-91
references.pmid: 15117972
references.citation: Br J Haematol. 2004 May;125(4):435-54
references.pmid: 15142114
references.citation: Nat Med. 2004 Sep;10(9):987-92
references.pmid: 15286785
references.citation: Br J Haematol. 1987 May;66(1):45-7
references.pmid: 3297128
references.citation: Cell Immunol. 1987 Oct 15;109(2):429-36
references.pmid: 2959376
references.citation: Transplantation. 1988 Aug;46(2):238-40
references.pmid: 3043780
references.citation: Proc Natl Acad Sci U S A. 1990 Aug;87(16):6301-5
references.pmid: 2117278
references.citation: J Immunol. 1992 Jan 1;148(1):35-40
references.pmid: 1530797
references.citation: Blood. 2004 Oct 1;104(7):2187-93
references.pmid: 15172973
references.citation: J Clin Invest. 2004 Oct;114(7):979-87
references.pmid: 15467837
references.citation: Adv Immunol. 1976;22:119-221
references.pmid: 56872
references.citation: J Immunol. 1986 May 15;136(10):3543-8
references.pmid: 2871104
references.citation: J Immunol. 1986 May 15;136(10):3549-52
references.pmid: 3486213
references.citation: J Exp Med. 1998 Jul 20;188(2):387-92
references.pmid: 9670050
references.citation: J Immunol. 1998 Nov 1;161(9):4467-71
references.pmid: 9794367
references.citation: Bone Marrow Transplant. 1998 Nov;22(9):873-81
references.pmid: 9827815
references.citation: Blood. 1999 Jul 15;94(2):390-400
references.pmid: 10397705
references.citation: Science. 1999 Jul 16;285(5426):412-5
references.pmid: 10411505
references.citation: Blood. 1999 Aug 1;94(3):932-9
references.pmid: 10419884
references.citation: Blood. 1999 Sep 1;94(5):1803-13
references.pmid: 10477707
references.citation: J Exp Med. 1993 Sep 1;178(3):805-14
references.pmid: 8394404