TY - JOUR
T1 - Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans
AU - Flynn, Ryan
AU - Du, Jing
AU - Veenstra, Rachelle G.
AU - Reichenbach, Dawn K.
AU - Panoskaltsis-Mortari, Angela
AU - Taylor, Patricia A.
AU - Freeman, Gordon J.
AU - Serody, Jonathan S.
AU - Murphy, William J.
AU - Munn, David H.
AU - Sarantopoulos, Stefanie
AU - Luznik, Leo
AU - Maillard, Ivan
AU - Koreth, John
AU - Cutler, Corey
AU - Soiffer, Robert J.
AU - Antin, Joseph H.
AU - Ritz, Jerome
AU - Dubovsky, Jason A.
AU - Byrd, John C.
AU - MacDonald, Kelli P.
AU - Hill, Geoff R.
AU - Blazar, Bruce R.
PY - 2014/6/19
Y1 - 2014/6/19
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2014-03-562231
DO - 10.1182/blood-2014-03-562231
M3 - Article
C2 - 24820310
AN - SCOPUS:84902668500
SN - 0006-4971
VL - 123
SP - 3988
EP - 3998
JO - Blood
JF - Blood
IS - 25
ER -