TY - JOUR
T1 - Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression
AU - Albring, Jörn C.
AU - Sandau, Michelle M.
AU - Rapaport, Aaron S.
AU - Edelson, Brian T.
AU - Satpathy, Ansuman
AU - Mashayekhi, Mona
AU - Lathrop, Stephanie K.
AU - Hsieh, Chyi Song
AU - Stelljes, Matthias
AU - Colonna, Marco
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
PY - 2010/11/22
Y1 - 2010/11/22
N2 - Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4+ forkhead box P3- (Foxp3-) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4+ Foxp3+ regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non-life-threatening diseases.
AB - Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4+ forkhead box P3- (Foxp3-) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4+ Foxp3+ regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non-life-threatening diseases.
UR - http://www.scopus.com/inward/record.url?scp=78649394507&partnerID=8YFLogxK
U2 - 10.1084/jem.20102017
DO - 10.1084/jem.20102017
M3 - Article
C2 - 21078889
AN - SCOPUS:78649394507
SN - 0022-1007
VL - 207
SP - 2551
EP - 2559
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -