Induction of Lethal Graft-versus-Host Disease by Anti-CD137 Monoclonal Antibody in Mice Prone to Chronic Graft-versus-Host Disease Wonyoung Kim, Juyang.

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Induction of Lethal Graft-versus-Host Disease by Anti-CD137 Monoclonal Antibody in Mice Prone to Chronic Graft-versus-Host Disease Wonyoung Kim, Juyang Kim, Daehee Jung, Hyuna Kim, Hye-Jung Choi, Hong R. Cho, Byungsuk Kwon Biology of Blood and Marrow Transplantation Volume 15, Issue 3, Pages 306-314 (March 2009) DOI: 10.1016/j.bbmt.2008.11.035 Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Anti-CD137 mAb induces aGVHD when given during the induction phase of cGVHD. Balb/c recipient mice were irradiated with 750 cGy and reconstituted with 5 × 106 BM cells and 1 × 107 purified CD4+ T cells from B10.D2 donor mice. Anti-CD137 mAb (200 μg per mouse) was administered immediately after transfer of donor cells (n = 10 per group). A, Loss of body weight. *P < .05 between the 2 groups at the indicated time points. B, Percent survival. **P < .01 between the 2 groups. C and D, Pathological scores of colons and livers (n = 7 to 10 per group). Colons and livers were harvested 7 days after disease induction, and H & E–stained colon (C) and liver (D) sections were scored for pathology. *P < .05 between the 2 groups. E and F, Expression of IFN-γ (G) and TNF-α (H) in colons at various times after disease induction and antibody treatment (n= 3 to 5 per group). RNA was extracted from colons, and RT-PCR was performed. Expression levels of cytokines were normalized to those of GAPDH. **P < .01 and ***P < .001 between the 2 groups at the indicated times. The results are representative of more than 3 independent experiments. Biology of Blood and Marrow Transplantation 2009 15, 306-314DOI: (10.1016/j.bbmt.2008.11.035) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Anti-CD137 mAb exacerbates cGVHD induced by donor CD4+ and CD8+ T cells. Balb/c recipient mice were irradiated with 750 cGy and reconstituted with 5 ×106 BM and 6 × 106 spleen/lymph node cells isolated from B10.D2 donor mice. Immediately thereafter, 200 μg of anti-CD137 mAb or control Ig was injected. A, Changes in body weight. **P < .01 and ***P < .001 between the 2 groups at the indicated time points (n = 9 or 10 per group). B, Percent survival. C, Mean clinical scores. D, Incidence of cGVHD. Experiments were repeated more than 3 times. Biology of Blood and Marrow Transplantation 2009 15, 306-314DOI: (10.1016/j.bbmt.2008.11.035) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Anti-CD137mAb activates donor CD8+ T cells. Balb/c recipient mice were irradiated with 750 cGy and reconstituted with 5 × 106 BM and 6 × 106 CD8+ T cells purified from B10.D2 donor mice. Immediately thereafter, 200 μg of anti-CD137 mAb or control Ig was injected. A, Changes in body weight. *P < .05 between the 2 groups from day 12 onward except day 37 (n = 10 per group). B, Percent survival. C, Mean clinical scores. **P < .01 and ***P < .001 between the 2 groups at the indicated time points. D, Incidence of cGVHD. **P < .01 between the 2 groups. E and F, H & E staining of skin and colon sections (E) and pathological scores of the colon (F). Samples were harvested on day 58 after disease induction (n = 6 or 7 per group). The experiments were repeated, and similar data were obtained. Biology of Blood and Marrow Transplantation 2009 15, 306-314DOI: (10.1016/j.bbmt.2008.11.035) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Inhibition of acute mortality induced by anti-CD137 mAb in CD137-deficient mice. WT and CD137-deficient Balb/c mice were irradiated with 750 cGy and reconstituted with 5 × 106 BM and 6 × 106 spleen/lymph node cells isolated from B10.D2 donor mice. Immediately thereafter, 200 μg of anti-CD137 mAb or control Ig was injected. A, Changes in body weight. *P < .05, **P < .01, and ***P < .001 between control Ig-treated and anti-CD137-treated groups at the indicated time points (n =10 per group). B, Percent survival. *P < .05 between the indicated groups. C, Mean clinical scores. ***P < .001 between the control Ig-treated and antiCD137-treated groups at the indicated time points. Biology of Blood and Marrow Transplantation 2009 15, 306-314DOI: (10.1016/j.bbmt.2008.11.035) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 The toxic effect of anti-CD137 mAb is time-dependent. Balb/c recipient mice were irradiated with 750 cGy and reconstituted with 5 × 106 BM and 6 × 106 spleen/lymph node cells isolated from B10.D2 donor mice. Anti-CD137 mAb or control Ig was injected 12 (A-C) or 30 (D-F) days after disease induction. A and D, Changes in body weight. *P < .05 between the 2 groups at the indicated time points (n = 10 per group). B and E, Percent survival. *P < .05 between the 2 groups (n = 10 per group). C and F, Mean clinical scores. *P < .05 and **P < .01 between the 2 groups at the indicated time points (n = 10 per group). Biology of Blood and Marrow Transplantation 2009 15, 306-314DOI: (10.1016/j.bbmt.2008.11.035) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions