Figure 6.
Teduglutide confers protection to mice with defective PCs and decrease intestinal cell apoptosis without loss of GVL effects. (A) Percentage survival of Irgm-1−/− mice that underwent allo-HCT and were treated with teduglutide or vehicle (n = 9 per group) from day −3 to day 3. Survival curves shown an increased survival rate in mice with defective PCs treated with teduglutide. Results are shown from 2 independent experiments. P value was calculated using the Mantel-Cox test. (B) Histological scores from allo-HCT Irgm-1−/− mice, small and large intestine were analyzed on day 10. Results indicate lower organ damage when GVHD mice were treated with teduglutide (n = 4) in comparison with the vehicle-treated group (n = 3). Mice were treated with teduglutide or vehicle from day −3 until day +3 unless differently specified. Results are shown from 1 experiment. The P values were calculated using a 2-sided Mann-Whitney U test. (C) Gene expression–based arrays analyzed on day 10 from the small intestine of allo-HCT BALB/c mice treated from day −3 to day 10 indicates the downregulation of different cell death–related genes in the teduglutide-treated group. Results are shown from 1 experiment. (D) Caspase 3 expression analyzed by qPCR in the small intestine of allo-HCT BALB/c mice treated from day −3 to day 10 with teduglutide or vehicle. Results display a downregulation of caspase 3 in mice treated with teduglutide (n = 10) in comparison with the high caspase 3 expression during GVHD (n = 11). Results are shown from 2 independent experiments. The P values were calculated using the unpaired, 2-sided Student t test. (E) Percentage quantification of apoptotic nuclei determined by a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. BALB/c mice underwent allo-HCT and were treated with teduglutide or vehicle from day −3 to day 3. Small intestine samples were stained to detect DNA brakes. Results indicate less apoptotic cells in GVHD mice treated with teduglutide (n = 7) compared with GVHD mice treated with vehicle (n = 8). The P value was calculated using the unpaired, 2-sided Student t test. (F) Percentage survival of BALB/c-WEHI-3B leukemia-bearing mice that received allo-HCT/T cells and treatment with teduglutide or vehicle or BM and leukemia cells alone (n = 10 per group). Data are derived from 2 independent experiments. P value was calculated using the Mantel-Cox test. (G) Representative bioluminescence images taken on day 22 from BALB/c mice transplanted with Ba/F3-ITD Luc+ cells + allo-BM or Ba/F3-ITD Luc+ cells + allo-BM followed by T-cell transplantation on day 2 and treated with teduglutide or vehicle. Bioluminescence imaging signal indicates the tumor growth in mice according to the group. Representative data from 2 independent experiments. (H) Percentage survival of C57BL/6-AMLMLL PTD FLT3 ITD leukemia bearing mice that received allo-HCT + leukemia cells or in addition T cells and were treated with teduglutide or vehicle (n = 10 per group). Data are shown from 1 experiment. P value was calculated using the Mantel-Cox test.

Teduglutide confers protection to mice with defective PCs and decrease intestinal cell apoptosis without loss of GVL effects. (A) Percentage survival of Irgm-1−/− mice that underwent allo-HCT and were treated with teduglutide or vehicle (n = 9 per group) from day −3 to day 3. Survival curves shown an increased survival rate in mice with defective PCs treated with teduglutide. Results are shown from 2 independent experiments. P value was calculated using the Mantel-Cox test. (B) Histological scores from allo-HCT Irgm-1−/− mice, small and large intestine were analyzed on day 10. Results indicate lower organ damage when GVHD mice were treated with teduglutide (n = 4) in comparison with the vehicle-treated group (n = 3). Mice were treated with teduglutide or vehicle from day −3 until day +3 unless differently specified. Results are shown from 1 experiment. The P values were calculated using a 2-sided Mann-Whitney U test. (C) Gene expression–based arrays analyzed on day 10 from the small intestine of allo-HCT BALB/c mice treated from day −3 to day 10 indicates the downregulation of different cell death–related genes in the teduglutide-treated group. Results are shown from 1 experiment. (D) Caspase 3 expression analyzed by qPCR in the small intestine of allo-HCT BALB/c mice treated from day −3 to day 10 with teduglutide or vehicle. Results display a downregulation of caspase 3 in mice treated with teduglutide (n = 10) in comparison with the high caspase 3 expression during GVHD (n = 11). Results are shown from 2 independent experiments. The P values were calculated using the unpaired, 2-sided Student t test. (E) Percentage quantification of apoptotic nuclei determined by a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. BALB/c mice underwent allo-HCT and were treated with teduglutide or vehicle from day −3 to day 3. Small intestine samples were stained to detect DNA brakes. Results indicate less apoptotic cells in GVHD mice treated with teduglutide (n = 7) compared with GVHD mice treated with vehicle (n = 8). The P value was calculated using the unpaired, 2-sided Student t test. (F) Percentage survival of BALB/c-WEHI-3B leukemia-bearing mice that received allo-HCT/T cells and treatment with teduglutide or vehicle or BM and leukemia cells alone (n = 10 per group). Data are derived from 2 independent experiments. P value was calculated using the Mantel-Cox test. (G) Representative bioluminescence images taken on day 22 from BALB/c mice transplanted with Ba/F3-ITD Luc+ cells + allo-BM or Ba/F3-ITD Luc+ cells + allo-BM followed by T-cell transplantation on day 2 and treated with teduglutide or vehicle. Bioluminescence imaging signal indicates the tumor growth in mice according to the group. Representative data from 2 independent experiments. (H) Percentage survival of C57BL/6-AMLMLL PTD FLT3 ITD leukemia bearing mice that received allo-HCT + leukemia cells or in addition T cells and were treated with teduglutide or vehicle (n = 10 per group). Data are shown from 1 experiment. P value was calculated using the Mantel-Cox test.

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