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

Ryan Flynn, Jing Du, Rachelle G. Veenstra, Dawn K. Reichenbach, Angela Panoskaltsis-Mortari, Patricia A. Taylor, Gordon J. Freeman, Jonathan S. Serody, William J. Murphy, David H. Munn, Stefanie Sarantopoulos, Leo Luznik, Ivan Maillard, John Koreth, Corey Cutler, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Jason A. Dubovsky, John C. ByrdKelli P. MacDonald, Geoff R. Hill, Bruce R. Blazar

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3988-3998
Number of pages11
JournalBlood
Volume123
Issue number25
DOIs
StatePublished - Jun 19 2014

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Bronchiolitis Obliterans
Germinal Center
Graft vs Host Disease
Helper-Inducer T-Lymphocytes
Grafts
B-Lymphocytes
Cells
T-cells
Interleukin-21 Receptors
T-Lymphocytes
CD40 Ligand
Chemokine Receptors
Hematopoietic Stem Cell Transplantation
Stem cells
Monoclonal Antibodies
Maintenance
Ligands
Morbidity
Lung
Mortality

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Flynn, R., Du, J., Veenstra, R. G., Reichenbach, D. K., Panoskaltsis-Mortari, A., Taylor, P. A., ... Blazar, B. R. (2014). Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood, 123(25), 3988-3998. https://doi.org/10.1182/blood-2014-03-562231

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.; Blazar, Bruce R.

In: Blood, Vol. 123, No. 25, 19.06.2014, p. 3988-3998.

Research output: Contribution to journalArticle

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 2014, 'Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans', Blood, vol. 123, no. 25, pp. 3988-3998. https://doi.org/10.1182/blood-2014-03-562231
Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA et al. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood. 2014 Jun 19;123(25):3988-3998. https://doi.org/10.1182/blood-2014-03-562231
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. / Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. In: Blood. 2014 ; Vol. 123, No. 25. pp. 3988-3998.
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AU - Taylor, Patricia A.

AU - Freeman, Gordon J.

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AU - Soiffer, Robert J.

AU - Antin, Joseph H.

AU - Ritz, Jerome

AU - Dubovsky, Jason A.

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