Raimon Duran-Struuck, Isao Tawara, Kathi Lowler, Shawn G

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A Novel Role for the Semaphorin Sema4D in the Induction of Allo-responses Raimon Duran-Struuck, Isao Tawara, Kathi Lowler, Shawn G. Clouthier, Elizabeth Weisiger, Clare Rogers, Gary Luker, Atsushi Kumanogoh, Chen Liu, James L.M. Ferrara, Pavan Reddy Biology of Blood and Marrow Transplantation Volume 13, Issue 11, Pages 1294.e1-1294.e11 (November 2007) DOI: 10.1016/j.bbmt.2007.07.014 Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Deficiency of Sema4D decreases cytokine production of T cells and DCs and lowers T cell expansion in an allogeneic in vitro setting. BALB/c stimulators and T cells from either B6 wt (black bars, allogeneic), Sema4D−/− (gray bars, allogeneic), or BALB/c Tc (white bars, syngeneic) were used. A-C, BALB/c splenocytes irradiated and cocultured with either BALB/c, B6 wt, or Sema4D−/− T cells at a 2/1 stimulator/responder ratio. A, Proliferation (72 hours), B, IL-2 production (48 hours), C, IFN-γ (48 hours). D-E, TNF-α and IL12p70 levels measured from supernatants in 18-24 hour cocultures with nonirradiated CD11c+ BALB/c DCs and BALB/c T cells (white bar), B6 wt T cells (black bars), Sema4D−/− T cells (gray bar) at a 2:1 ratio. *P < .01, **P < .02. Biology of Blood and Marrow Transplantation 2007 13, 1294.e1-1294.e11DOI: (10.1016/j.bbmt.2007.07.014) Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Maintenance of CTL by Sema4D−/− T cells B6 wt (allogeneic H2b) or Sema4D−/− (allogeneic H2b) CD90+ T cells were cultured in vitro for 5 days with irradiated BALB/c (H2d) splenocytes (A) or transplanted into irradiated BALB/c mice (B) as described in Study Design. Splenocytes were harvested from the cultures on day +5-6 in the in vitro priming experiments (A) or from recipients (n = 5/group) on day +14 after BMT. CTL assays, normalized for total donor (H2b) CD8+ cells, and used in a 51Cr-release assay. Cytotoxic T lymphocyte activity against allo targets (P815) in wt allo-control (□) versus Sema4D−/− allo (▴) groups. Lysis in allo-geneic groups was similar, whereas no significant lysis of syngeneic targets (EL-4) observed in either of wt (●) or Sema4D−/− (♢)groups. Data from 1 of 2 similar experiments are shown. Biology of Blood and Marrow Transplantation 2007 13, 1294.e1-1294.e11DOI: (10.1016/j.bbmt.2007.07.014) Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Sema4D−/− T cell recipients have improved survival and clinical GVHD scores. A-F, BALB/c (allogeneic) or B6 (syngeneic) recipients were lethally irradiated (800 cGy) and intravenously given 5.0 × 106 B6 wt BM and either 5.0 × 105 wt B6 or Sema4D−/− T cells. A-C, On day +14 mice were humanely euthanized and A, spleens of recipient animals were analyzed for total H2b CD3+ T cells; B, serum IFN-γ levels; C, CD4+ and CD8+ donor derived (H2b) chimerism. D, survival, E, % weight loss, and F, GVHD scores compared to day +0. D-F, B6 (solid line), Sema4D−/− T cells (dashed line), and BALB/c (dotted line). #P < .01, *P < .05, **P < .02, ***P < .06. Results are representative of 1 of 3 similar experiments with a total of n = 18/allogeneic recipients of the control and SemaD4−/− donors. Biology of Blood and Marrow Transplantation 2007 13, 1294.e1-1294.e11DOI: (10.1016/j.bbmt.2007.07.014) Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Sema4D−/− T cell recipients have improved immune reconstitution and decreased GVHD target organ pathology. A-E, BALB/c (allogeneic) or B6 (syngeneic) recipients were irradiated with 800 cGy and intravenously given 5.0 × 106 B6 wt BM and either 5.0 × 105 wt B6 or Sema4D−/− T cells. n = 4 syn, n = 6 allogeneic control, n = 6 Sema4D−/− (A-C). Pathology scores of GVHD target organs on day + 60 post-BMT as described in Study Design of liver (A) small and large intestine (B), and skin (C). D, Splenic cellularity on day + 60 post-BMT. E, Donor (H2b) CD3+, CD4+, and CD8+ from recipient spleens on day + 60. Syngeneic recipients (white bars), allogeneic B6 wt Tc (black bars) and allogeneic recipients of Sema4D−/− B6 Tc recipients (gray bars). One of 2 similar experiments. *P < .03. Biology of Blood and Marrow Transplantation 2007 13, 1294.e1-1294.e11DOI: (10.1016/j.bbmt.2007.07.014) Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Sema4D−/− GVL effects. BALB/c (syngeneic H2d), B6 wt (allogeneic H2b), or Sema4D−/− (allogeneic H2b) recipients were irradiated with 800 cGy and intravenously given 5.0 × 106 BM cells from BALB/c (syngeneic) or wt B6 (allogeneic groups) mice, plus either 5.0 × 105 wt B6 (allogeneic control), Sema4D−/− T cells (experimental) or BALB/c T cells (syngeneic control). Four hundred P815 tumor cells were added into the BM inoculum of all groups. A syngeneic [BALB/c→BALB/c] control group did not receive a tumor. A, BLI images show progression of tumor growth systemically over 24 days n = 4/group. Tumor burden in Sema4D−/− T cell recipients is similar to B6 wt T cell recipients. B, Mean values ± SEM for photon flux/animal (n = 4 mice). C-D, Tumor-free survival n = 6 syngeneic without tumor, n = 10 syngeneic + P815, n = 10 allo B6 wt T cell recipients + P815 and n = 10 allo-Sema4D−/− T cell recipients + 400 P815 (C) or 1000 P815 (D). Improved tumor-free survival in allogeneic T cell recipients compared to the syngeneic recipients in both tumor challenges. Sema4D−/− allogeneic T cell recipients had a similar GVL effect as wt T cell control allogeneic recipients. *P < .01. Biology of Blood and Marrow Transplantation 2007 13, 1294.e1-1294.e11DOI: (10.1016/j.bbmt.2007.07.014) Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure S1 Biology of Blood and Marrow Transplantation 2007 13, 1294.e1-1294.e11DOI: (10.1016/j.bbmt.2007.07.014) Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions