title: Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.
abstract: Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Rachelle G
authors.initials: RG
authors.lastname: Veenstra
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Reichenbach
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Lineberger Comprehensive Cancer Center, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC;
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA;
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Department of Pediatrics, Georgia Health Sciences University, Augusta, GA;
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Lineberger Comprehensive Cancer Center, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sarantopoulos
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, The Johns Hopkins University, Baltimore, MD;
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Life Sciences Institute and Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH; and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH; and.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Kelli P
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Geoff R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D005434:Flow Cytometry; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000276:immunology / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013577:Syndrome; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D019013:CD40 Antigens; C513179:CXCR5 protein, mouse; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D054380:Receptors, CXCR5; D053655:Receptors, Interleukin-21; D023201:CD40 Ligand; D000098546:Interleukin-21