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Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.

Authors
  • Flynn, Ryan1
  • Du, Jing1
  • Veenstra, Rachelle G1
  • Reichenbach, Dawn K1
  • Panoskaltsis-Mortari, Angela1
  • Taylor, Patricia A1
  • Freeman, Gordon J2
  • Serody, Jonathan S3
  • Murphy, William J4
  • Munn, David H5
  • Sarantopoulos, Stefanie3
  • Luznik, Leo6
  • Maillard, Ivan7
  • Koreth, John2
  • Cutler, Corey2
  • Soiffer, Robert J2
  • Antin, Joseph H2
  • Ritz, Jerome2
  • Dubovsky, Jason A8
  • Byrd, John C8
  • And 3 more
  • 1 Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
  • 2 Dana-Farber Cancer Institute, Boston, MA;
  • 3 Lineberger Comprehensive Cancer Center, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC;
  • 4 Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA;
  • 5 Department of Pediatrics, Georgia Health Sciences University, Augusta, GA; , (Georgia)
  • 6 Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, The Johns Hopkins University, Baltimore, MD;
  • 7 Life Sciences Institute and Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan, Ann Arbor, MI;
  • 8 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH; and.
  • 9 Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia. , (Australia)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jun 19, 2014
Volume
123
Issue
25
Pages
3988–3998
Identifiers
DOI: 10.1182/blood-2014-03-562231
PMID: 24820310
Source
Medline
Language
English
License
Unknown

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. © 2014 by The American Society of Hematology.

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