Induction of lethal graft-versus-host disease by anti-CD137 monoclonal antibody in mice prone to chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. We previously showed that anti-CD137 monoclonal antibody (mAb) can cure advanced cGVHD by inducing activation-induced cell death of donor T cells. In this study, we examined whether administration of anti-CD137 mAb can prevent the development of cGVHD after bone marrow transplantation (BMT) in mice conditioned with total body irradiation (TBI). We used the B10.D2-->Balb/c (H-2(d)) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. A single injection of anti-CD137 mAb was administered immediately after BMT. In contrast to the results obtained from the curing model of cGVHD, anti-CD137 given simultaneously with BMT resulted in lethal GVHD. Histopathologic evaluation revealed inflammation and damage of target organs from acute GVHD (aGVHD) in anti-CD137-treated mice. Anti-CD137-induced lethal aGVHD required host cells, as well as irradiation and mature donor T cells. Apparently, anti-CD137 mAb rapidly induced activation of donor T cells and sustained their activation status under the inflammatory condition triggered by irradiation. When given on day 12 after irradiation and BMT, anti-CD137 mAb could still exacerbate GVHD, but when given on day 30, it could not. Our data demonstrate that anti-CD137 mAb can amplify inflammation induced by host preconditioning, subsequently resulting in lethal aGVHD; thus, alleviating irradiation-induced toxicity is critical to allow the use of anti-CD137 mAb as GVHD prophylaxis.
Kim
Wonyoung
W
Department of Biological Science, University of Ulsan, Ulsan, Republic of Korea.
Kim
Juyang
J
Jung
Daehee
D
Kim
Hyuna
H
Choi
Hye-Jung
HJ
Cho
Hong R
HR
Kwon
Byungsuk
B
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007420:Intestine, Large / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D033581:Stem Cell Transplantation / Q000009:adverse effects; D019172:Transplantation Conditioning / Q000009:adverse effects; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma