title: Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans.
abstract: Chronic GVHD (cGVHD) poses a significant risk for HSCT patients. Preclinical development of new therapeutic modalities has been hindered by models with pathologic findings that may not simulate the development of human cGVHD. Previously, we have demonstrated that cGVHD induced by allogeneic HSCT after a conditioning regimen of cyclophosphamide and total-body radiation results in pulmonary dysfunction and airway obliteration, which leads to bronchiolitis obliterans (BO), which is pathognomonic for cGVHD of the lung. We now report cGVHD manifestations in a wide spectrum of target organs, including those with mucosal surfaces. Fibrosis was demonstrated in the lung and liver and was associated with CD4(+) T cells and B220(+) B-cell infiltration and alloantibody deposition. Donor bone marrow obtained from mice incapable of secreting IgG alloantibody resulted in less BO and cGVHD. Robust germinal center reactions were present at the time of cGVHD disease initiation. Blockade of germinal center formation with a lymphotoxin-receptor-immunoglobulin fusion protein suppressed cGVHD and BO. We conclude that cGVHD is caused in part by alloantibody secretion, which is associated with fibrosis and cGVHD manifestations including BO, and that treatment with a lymphotoxin-β receptor-immunoglobulin fusion protein could be beneficial for cGVHD prevention and therapy.
authors.affiliation: Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Mathangi
authors.initials: M
authors.lastname: Srinivasan
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.forename: Andrew
authors.initials: A
authors.lastname: Price
authors.forename: Ann
authors.initials: A
authors.lastname: Ranger
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001782:Blood Donors; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D005455:Fluorescent Antibody Technique; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology
chemical_list: D007074:Immunoglobulin G; D007518:Isoantibodies; D053259:Lymphotoxin beta Receptor; D011993:Recombinant Fusion Proteins; D017493:Leukocyte Common Antigens
references.citation: Biol Blood Marrow Transplant. 2003 Oct;9(10):657-66
references.pmid: 14569562
references.citation: Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S106-14
references.pmid: 19896545
references.citation: Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S146-51
references.pmid: 19836455
references.citation: J Clin Invest. 2005 Nov;115(11):3072-82
references.pmid: 16276416
references.citation: J Dent Res. 2004 Feb;83(2):98-103
references.pmid: 14742644
references.citation: Biol Blood Marrow Transplant. 2010 Oct;16(10):1362-9
references.pmid: 20353829
references.citation: Haematologica. 2008 Nov;93(11):1702-11
references.pmid: 18728020
references.citation: Am J Respir Crit Care Med. 2007 Oct 1;176(7):713-23
references.pmid: 17575098
references.citation: Bone Marrow Transplant. 2000 May;25(10):1073-8
references.pmid: 10828868
references.citation: Nat Rev Drug Discov. 2006 Jul;5(7):564-76
references.pmid: 16816838
references.citation: Clin Chest Med. 1993 Dec;14(4):741-9
references.pmid: 8313677
references.citation: J Exp Med. 1999 May 17;189(10):1639-48
references.pmid: 10330443
references.citation: Clin Cancer Res. 2007 Oct 15;13(20):6107-14
references.pmid: 17947475
references.citation: Biol Blood Marrow Transplant. 2008 Apr;14(4):365-78
references.pmid: 18342778
references.citation: Curr Opin Oncol. 2006 Mar;18(2):115-9
references.pmid: 16462178
references.citation: J Allergy Clin Immunol. 2010 Nov;126(5):898-907; quiz 908-9
references.pmid: 21050940
references.citation: Biol Blood Marrow Transplant. 2003 Aug;9(8):505-11
references.pmid: 12931119
references.citation: Immunol Rev. 2008 Jun;223:202-20
references.pmid: 18613838
references.citation: J Immunol. 2002 Mar 15;168(6):3088-98
references.pmid: 11884483
references.citation: Blood. 2006 Apr 1;107(7):2993-3001
references.pmid: 16352808
references.citation: J Immunol. 2006 Apr 15;176(8):4515-9
references.pmid: 16585539
references.citation: Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56
references.pmid: 16338616
references.citation: Transplantation. 2001 Oct 27;72(8):1354-62
references.pmid: 11685103
references.citation: Biol Blood Marrow Transplant. 2009 Sep;15(9):1005-13
references.pmid: 19660713
references.citation: Biol Blood Marrow Transplant. 2007 Apr;13(4):386-97
references.pmid: 17382246
references.citation: Nat Med. 2011 May;17(5):596-603
references.pmid: 21499267
references.citation: Blood. 2004 Oct 15;104(8):2603-6
references.pmid: 15251978
references.citation: J Immunol. 2005 Mar 15;174(6):3781-8
references.pmid: 15749919
references.citation: Curr Opin Hematol. 2006 Nov;13(6):426-35
references.pmid: 17053454
references.citation: Blood. 2011 Feb 17;117(7):2265-74
references.pmid: 21063025
references.citation: Blood. 2007 Jul 1;110(1):237-41
references.pmid: 17363728
references.citation: Blood. 2008 Mar 15;111(6):3276-85
references.pmid: 17925486
references.citation: Blood. 2005 Apr 1;105(7):2973-8
references.pmid: 15613541
references.citation: Nat Rev Immunol. 2003 Aug;3(8):642-55
references.pmid: 12974479
references.citation: Blood. 2001 Sep 1;98(5):1601-6
references.pmid: 11520813
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4766-71
references.pmid: 10781082
references.citation: J Immunol. 2005 Apr 1;174(7):4389-99
references.pmid: 15778404
references.citation: Blood. 2006 Jul 15;108(2):756-62
references.pmid: 16551963
references.citation: Blood. 2009 Apr 16;113(16):3865-74
references.pmid: 19168788
references.citation: J Immunol. 2005 Jan 15;174(2):817-26
references.pmid: 15634903
references.citation: Pediatr Clin North Am. 2010 Feb;57(1):297-322
references.pmid: 20307722
references.citation: Eur J Cardiothorac Surg. 2006 Dec;30(6):846-51
references.pmid: 17055283
references.citation: Blood. 1998 Nov 15;92(10):3949-59
references.pmid: 9808589