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Blood. 2014 Jun 19;123(25):3988-98. doi: 10.1182/blood-2014-03-562231. Epub 2014 May 12.

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

Author information

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;
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.

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.

PMID:
24820310
PMCID:
PMC4064335
DOI:
10.1182/blood-2014-03-562231
[Indexed for MEDLINE]
Free PMC Article

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