Journal
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Volume 15, Issue 3, Pages 306-314Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2008.11.035
Keywords
Chronic craft-versus-host disease; Graft-versus-host disease prophylaxis; CD137
Categories
Funding
- Korea Research Foundation [E00010, J00302]
- National R&D Program for Cancer Control [0820240]
- Korean Ministry of Health and Welfare [A040004]
- Korea Health Promotion Institute [0820240] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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