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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Flynn, R; Du, J; Veenstra, RG; Reichenbach, DK; Panoskaltsis-Mortari, A; Taylor, PA; Freeman, GJ; Serody, JS; Murphy, WJ; Munn, DH; Sarantopoulos, S; Luznik, L; Maillard, I; Koreth, J; Cutler, C; Soiffer, RJ; Antin, JH; Ritz, J; Dubovsky, JA; Byrd, JC; MacDonald, KP; Hill, GR; Blazar, BR

Published Date

  • June 2014

Published In

Volume / Issue

  • 123 / 25

Start / End Page

  • 3988 - 3998

PubMed ID

  • 24820310

Pubmed Central ID

  • 24820310

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2014-03-562231

Language

  • eng