Therapeutic Benefit of Bortezomib on Acute Graft-versus-Host Disease Is Tissue Specific and Is Associated with Interleukin-6 Levels Chien-Chun Steven.

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Therapeutic Benefit of Bortezomib on Acute Graft-versus-Host Disease Is Tissue Specific and Is Associated with Interleukin-6 Levels Chien-Chun Steven Pai, Hui-Hua Hsiao, Kai Sun, Mingyi Chen, Takeshi Hagino, Joseph Tellez, Christine Mall, Bruce R. Blazar, Arta Monjazeb, Mehrdad Abedi, William J. Murphy Biology of Blood and Marrow Transplantation Volume 20, Issue 12, Pages 1899-1904 (December 2014) DOI: 10.1016/j.bbmt.2014.07.022 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Characteristics of murine GVHD in MHC-matched miHA-mismatched model. C57BL/6 recipient mice received 950 cGy myeloablative dose of TBI from a 137Cs source. A dose of 1.0 × 107 donor C3H.SW TCD-BM cells was infused with or without 2 to 3 × 106 donor C3H.SW–purified CD8+ T cells after TBI. GVHD target samples (gut, skin, and liver) were harvested and stained with H & E. The grading of histopathological GVHD damage in recipients that had undergone transplantation was assessed according to the scoring system described in the Methods section. Serum samples were taken by cardiac punctures and stored for analysis. (A) Representative histopathologic examination of H & E–stained sections of paraffin-embedded skin, liver, and gut tissues. Arrows indicate erosion of epidermis with inflammatory infiltrate in the skin and arrowheads indicate marked inflammatory infiltration over portal triads in the liver. (B) Semiquantitative histologic grading (grade 0 to 4) of different target tissues. (C) Liver pathology scores were graded from 1 to 4 and were shown as percentage between skin and liver GVHD and liver GVHD only groups. (D) Serum IL-6 level was examined in skin and liver GVHD, compared with liver only or TCD-BM only groups. (E) Relative RNA expression of IL-6 levels in the skin. (F) Relative RNA expression of IL-6 levels in the liver. All the data were collected from 2 or 3 independent experiments with at least 8 mice (n = 8) per group. Data were analyzed by 1-way ANOVA or Student's t-tests to determine if mean values were significantly different. P < .05 (*), P < .001 (***), P < .0001 (****) were considered significant. Biology of Blood and Marrow Transplantation 2014 20, 1899-1904DOI: (10.1016/j.bbmt.2014.07.022) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Tissue-specific protection by continuous application of bortezomib with decreased skin, but not liver, GVHD is associated with serum IL-6 level. C57BL/6 recipient mice received 950 cGy myeloablative dose of TBI from a 137Cs source. A dose of 1.0 × 107 donor C3H.SW BM cells was infused with or without 2 to 3 × 106 donor C3H.SW-purified CD8+ T cells after TBI. Recipient C57BL/6 mice then received PBS or bortezomib at a dose of .125 mg/kg i.p. after BMT. (A) Representative clinical pictures of skin GVHD. (B) Skin clinical scores were evaluated twice a week. (C) Body weight changes among different groups. (D) Representative H & E stained sections of paraffin-embedded skin and liver from recipients. Arrows indicate erosion of epidermis with inflammation infiltrate. Arrowheads indicate inflammatory infiltration over portal triads in the liver. (E-F) Semiquantitative histological analysis (grade 0 to 4) of at least 6 examined recipients in each organ. (G) Liver enzymes from recipients with or without bortezomib therapy and TCD-BM control groups. (H) Serum IL-6 levels of recipients with or without bortezomib therapy were analyzed. All the data were collected from 2 independent experiments with at least 6 mice (n = 6) per group. Data were analyzed by 1-way ANOVA and post-hoc Tukey test to determine if mean values were significant among groups. P < .05 (*) and P < .01(**) were considered significant. Biology of Blood and Marrow Transplantation 2014 20, 1899-1904DOI: (10.1016/j.bbmt.2014.07.022) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Anti–IL-6 therapy in skin GVHD model. C57BL/6 recipient mice received 950 cGy TBI and underwent transplantation with TCD-BM with or without purified CD8+ T cells. Anti–IL-6 antibody or isotype control was given at a dose of 1 mg/mouse i.p. after BMT and every week thereafter. (A) Representative histopathologic scores were examined from paraffin-embedded skin and liver from recipients with or without anti–IL-6 therapy and TCD-BM control groups. (B) Liver enzymes from recipients with or without anti–IL-6 therapy and TCD-BM control groups. (C) Skin tissues were analyzed for IL-6 expression levels by qRT-PCR. (D) Skin samples were harvested and digested into single cell suspension for flow cytometry analysis. (E) Total numbers of CD45+CD8+ T cell in the skin tissues. (F) CD45+CD8+CXCR3+ T cells in spleen after BMT with different treatments. (G) Total numbers of CD45+CD8+CXCR3+ T cells in spleen. (H) Total numbers of Treg cells were determined by flow cytometry in skin. (I) Survival curve among different treatment groups. All the data were collected from 2 to 3 independent experiments with at least 5 mice (n = 5) per group. Data were analyzed by 1-way ANOVA with post-hoc Tukey test. Survival curves were pooled from 2 to 3 independent experiments with 14 to 18 mice per group and plotted by the Kaplan-Meier method and analyzed by the log-rank test. P < .05 (*), P < .01 (**), P < .001 (***) were considered significant. Biology of Blood and Marrow Transplantation 2014 20, 1899-1904DOI: (10.1016/j.bbmt.2014.07.022) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions