TY - JOUR
T1 - Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells
AU - Coghill, James M.
AU - Carlson, Michael J.
AU - Panoskaltsis-Mortari, Angela
AU - West, Michelle L.
AU - Burgents, Joseph E.
AU - Blazar, Bruce R.
AU - Serody, Jonathan S.
PY - 2010/6/10
Y1 - 2010/6/10
N2 - CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7-/-) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7-/- T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7-/- T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7-/- T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7-/- T cells were capable of generating robust graftversus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7-/- regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.
AB - CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7-/-) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7-/- T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7-/- T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7-/- T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7-/- T cells were capable of generating robust graftversus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7-/- regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.
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U2 - 10.1182/blood-2009-08-239848
DO - 10.1182/blood-2009-08-239848
M3 - Article
C2 - 20185583
AN - SCOPUS:77954734137
SN - 0006-4971
VL - 115
SP - 4914
EP - 4922
JO - Blood
JF - Blood
IS - 23
ER -