Repifermin (keratinocyte growth factor-2) reduces the severity of graft-versus-host disease while preserving a graft-versus-leukemia effect Shawn G Clouthier,

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Repifermin (keratinocyte growth factor-2) reduces the severity of graft-versus-host disease while preserving a graft-versus-leukemia effect Shawn G Clouthier, Kenneth R Cooke, Takanori Teshima, Kathleen P Lowler, Chen Liu, Kevin Connolly, James L.M Ferrara Biology of Blood and Marrow Transplantation Volume 9, Issue 9, Pages 592-603 (September 2003) DOI: 10.1016/S1083-8791(03)00230-1

Figure 1 Effects of repifermin on histologic and biochemical markers of GVHD. Recipient mice (B6D2F1) underwent transplantation with 5 × 106 bone marrow cells and 0.5 × 106 T cells from syngeneic (B6D2F1) or allogeneic (B6) mice after conditioning with 1500 cGy of TBI administered via split dose. Repifermin (5 mg/kg) or control diluent was given intraperitoneally once daily from day −3 to day +7. Small-bowel samples were taken for histology 7 days after BMT from (A) syngeneic BMT controls, (B) allogeneic BMT controls, and (C) allogeneic BMT- and repifermin-treated cohorts. Pathologic features were scored in a blinded fashion (by C.L.) and summed as described in Materials and Methods. Allogeneic BMT control mouse bowel exhibited severe disruption of the intestinal architecture, including villous blunting, lymphocytic infiltration, and significant crypt destruction. Serum LPS (D) □ syngeneic, n = 8; ■ allogeneic, n = 22; ▩ allogeneic + repifermin, n = 21) and TNFα (E) (□ syngeneic, n = 8; ■ allogeneic, n = 22; ▩ allogeneic + repifermin, n = 17) were measured 7 days after BMT in syngeneic and allogeneic recipient mice treated with either repifermin (5 mg/kg/d from day −3 to day +7) or diluent only ■ versus ▩, ∗P = .03). Biology of Blood and Marrow Transplantation 2003 9, 592-603DOI: (10.1016/S1083-8791(03)00230-1)

Figure 2 Repifermin enhances post-BMT survival and reduces GVHD after allogeneic BMT. Mice underwent transplantation as in Figure 1. Repifermin (5 mg/kg) or control diluent was given intraperitoneally daily from day −3 to +7 as shown by the bar on the x axis. A, Survival estimates are shown by Kaplan-Meier cumulative curves obtained by combining results for 2 similar experiments (■ syngeneic, n = 10; • allogeneic, n = 22; ▵ allogeneic + repifermin, n = 17). B, The clinical GVHD scores (■ syngeneic, n = 10; • allogeneic, n = 22; ▵ allogeneic + repifermin, n = 17) for all mice were determined by summing 5 parameters as described in Materials and Methods and plotted as mean ± SEM. ∗P < .01. Biology of Blood and Marrow Transplantation 2003 9, 592-603DOI: (10.1016/S1083-8791(03)00230-1)

Figure 3 Effects of 6-week administration of repifermin after BMT. Recipient mice underwent transplantation as in Figure 1. Repifermin (5 mg/kg) or control diluent was given from day −3 to day +42 as denoted by the bold portion of the x axis. A, Survival estimates are shown by Kaplan-Meier cumulative curves obtained by combining results for 2 similar experiments (■ syngeneic, n = 12; • allogeneic, n = 16; ▵ allogeneic + repifermin [5 mg/kg], n = 16. B, The clinical GVHD scores expressed as mean ± SEM (■ syngeneic, n =12; • allogeneic, n =16; ▵ allogeneic + repifermin [5 mg/kg], n = 16) for all mice are reported as before. ∗P < .001. Biology of Blood and Marrow Transplantation 2003 9, 592-603DOI: (10.1016/S1083-8791(03)00230-1)

Figure 4 Repifermin effects on CTL activity after BMT. Mice underwent transplantation as in Figure 1 and received either diluent or repifermin from day −3 to +7. On day +13 after BMT, mouse splenocytes were used as effectors in a CTL assay as described in Materials and Methods. Splenocytes were pooled from 3 to 5 mice per group. Data represent mean ± SD from 1 of 3 similar experiments. Biology of Blood and Marrow Transplantation 2003 9, 592-603DOI: (10.1016/S1083-8791(03)00230-1)

Figure 5 Repifermin preserves an allogeneic GVL effect. B6D2F1 recipient mice were conditioned and underwent transplantation as described in Figure 1. A total of 2000 P815 (H-2d) tumor cells were added to the bone marrow inoculum on day 0. Mice received either TCD bone marrow (solid symbols) or bone marrow plus T cells and injections of diluent (circles) or repifermin (squares) as indicated with the black bar along the x axis. Results are represented by Kaplan-Meier cumulative survival curve estimates combining 2 similar experiments (• allogeneic TCD, n =8; ■ allogeneic TCD + repifermin, n =12; ○ allogeneic, n =27; □ allogeneic + repifermin, n =20, □ versus ○, P = .04). Biology of Blood and Marrow Transplantation 2003 9, 592-603DOI: (10.1016/S1083-8791(03)00230-1)