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

Flynn, Ryan, Du, Jing, Veenstra, Rachelle G., Reichenbach, Dawn K., Panoskaltsis-Mortari, Angela, Taylor, Patricia A., Freeman, Gordon J., Serody, Jonathan S., Murphy, William J., Munn, David H., Sarantopoulos, Stefanie, Luznik, Leo, Maillard, Ivan, Koreth, John, Cutler, Corey, Soiffer, Robert J., Antin, Joseph H., Ritz, Jerome, Dubovsky, Jason A., Byrd, John C., MacDonald, Kelli P., Hill, Geoff R. and Blazar, Bruce R. (2014) Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood, 123 25: 3988-3998. doi:10.1182/blood-2014-03-562231

Author Flynn, Ryan
Du, Jing
Veenstra, Rachelle G.
Reichenbach, Dawn K.
Panoskaltsis-Mortari, Angela
Taylor, Patricia A.
Freeman, Gordon J.
Serody, Jonathan S.
Murphy, William J.
Munn, David H.
Sarantopoulos, Stefanie
Luznik, Leo
Maillard, Ivan
Koreth, John
Cutler, Corey
Soiffer, Robert J.
Antin, Joseph H.
Ritz, Jerome
Dubovsky, Jason A.
Byrd, John C.
MacDonald, Kelli P.
Hill, Geoff R.
Blazar, Bruce R.
Title Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans
Journal name Blood   Check publisher's open access policy
ISSN 1528-0020
Publication date 2014-06-19
Year available 2014
Sub-type Article (original research)
DOI 10.1182/blood-2014-03-562231
Open Access Status Not yet assessed
Volume 123
Issue 25
Start page 3988
End page 3998
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
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) formationandimmunoglobulin 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.
Keyword Hematology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P01 CA142106-06A1
P01 AI 056299
T32 HL 00706237
S10 RR16851
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 61 times in Thomson Reuters Web of Science Article | Citations
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