Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease.
Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.
Ordemann
Rainer
R
Blood and Marrow Transplant Program, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, Michigan 48109-0942, USA.
Hutchinson
Raymond
R
Friedman
Jeffrey
J
Burakoff
Steven J
SJ
Reddy
Pavan
P
Duffner
Ulrich
U
Braun
Thomas M
TM
Liu
Chen
C
Teshima
Takanori
T
Ferrara
James L M
JL
D000375:Aging / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000097:blood; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha