TY - JOUR
T1 - Secondary Lymphoid Organs Contribute to, but Are Not Required for the Induction of Graft-versus-Host Responses following Allogeneic Bone Marrow Transplantation
T2 - A shifting Paradigm for T Cell Allo-activation
AU - Silva, Ines A.
AU - Olkiewicz, Krystyna
AU - Askew, David
AU - Fisher, Jacquelyn M.
AU - Chaudhary, Meghana N.
AU - Vannella, Kevin M.
AU - Deurloo, Daphne T.
AU - Choi, Sung W.
AU - Pierce, Elizabeth M.
AU - Clouthier, Shawn G.
AU - Liu, Chen
AU - Cooke, Kenneth R.
N1 - Funding Information:
Financial disclosure: Dr. Cooke is an Amy Strelzer-Manasevit Scholar of the National Marrow Program, a Clinical Scholar of the Leukemia and Lymphoma Society, and the recipient of a Clinical Scientist in Translational Research Award from the Burroughs Wellcome Fund. This work was supported in part by the Walther Cancer Institute.
PY - 2010/5
Y1 - 2010/5
N2 - Graft-versus-host disease (GVHD) remains the major complication of allogeneic bone marrow transplantation (allo-BMT). GVHD fundamentally depends upon the activation of donor T cells by host antigen-presenting cells (APCs), but the precise location of these interactions remains uncertain. We examined the role of secondary lymphoid organs (SLO) in the induction of GVHD by using homozygous aly/aly mice that are deficient in lymph nodes (LNs) and Peyer's patches (PPs). Lethally irradiated, splenectomized, aly/aly (LN/PP/Sp-/-) mice and sham-splenectomized, aly/+ (LN/PP/Sp+/+) mice received BMT from either syngeneic (aly/aly) or allogeneic, major histocompatibility complex (MHC) disparate donors. Surprisingly, although LN/PP/Sp-/- allo-BMT recipients experience a survival advantage, they developed significant systemic and target organ GVHD that is comparable to LN/PP/Sp+/+ controls. Early after allo-BMT, the activation and proliferation of donor T cells was significantly greater in the BM cavity of LN/PP/Sp-/- mice compared to LN/PP/Sp+/+ controls. Donor T cells in LN/PP/Sp-/- mice demonstrated cytolytic activity in vitro, but Graft vs Leukemia (GVL) activity could be overcome by increasing the tumor burden. These data suggest that SLO contribute to, but are not required for, allogeneic T cell responses, and suggest that the BM may represent an alternative, albeit less efficient site for T cell activation following allo-BMT.
AB - Graft-versus-host disease (GVHD) remains the major complication of allogeneic bone marrow transplantation (allo-BMT). GVHD fundamentally depends upon the activation of donor T cells by host antigen-presenting cells (APCs), but the precise location of these interactions remains uncertain. We examined the role of secondary lymphoid organs (SLO) in the induction of GVHD by using homozygous aly/aly mice that are deficient in lymph nodes (LNs) and Peyer's patches (PPs). Lethally irradiated, splenectomized, aly/aly (LN/PP/Sp-/-) mice and sham-splenectomized, aly/+ (LN/PP/Sp+/+) mice received BMT from either syngeneic (aly/aly) or allogeneic, major histocompatibility complex (MHC) disparate donors. Surprisingly, although LN/PP/Sp-/- allo-BMT recipients experience a survival advantage, they developed significant systemic and target organ GVHD that is comparable to LN/PP/Sp+/+ controls. Early after allo-BMT, the activation and proliferation of donor T cells was significantly greater in the BM cavity of LN/PP/Sp-/- mice compared to LN/PP/Sp+/+ controls. Donor T cells in LN/PP/Sp-/- mice demonstrated cytolytic activity in vitro, but Graft vs Leukemia (GVL) activity could be overcome by increasing the tumor burden. These data suggest that SLO contribute to, but are not required for, allogeneic T cell responses, and suggest that the BM may represent an alternative, albeit less efficient site for T cell activation following allo-BMT.
KW - Antigen presentation
KW - Cytotoxicity
KW - Graft-versus-leukemia
KW - Immunity
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=77951146832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951146832&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2009.12.007
DO - 10.1016/j.bbmt.2009.12.007
M3 - Article
C2 - 20117226
AN - SCOPUS:77951146832
SN - 1083-8791
VL - 16
SP - 598
EP - 611
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 5
ER -