Figure 3.
IL-6 trans signaling increases late after transplantation and regulates cutaneous GVHD. (A-D) Lethally irradiated B6 wild-type (B6.WT) mice received 10 × 106 BM and 5 × 106 T-cell grafts from BALB/c mice. Peripheral blood serum levels of IL-6 (A), sIL-6R (required for IL-6 trans signaling) (B), and sgp130 (antagonist of IL-6 trans signaling) (C) were analyzed from naïve B6 mice and B6 mice receiving transplants at the indicated times after transplantation (n = 6-28 mice per group from 1-4 experiments). (D) Molar ratio of sIL-6R (∼40 kDa) to sgp130 (∼100 kDa) from matched samples in panels B and C, with a higher ratio indicating a greater incidence of IL-6 trans signaling (box and Tukey whiskers). (E-O) The role of IL-6 trans signaling in GVHD was assessed in preclinical models of acute (E-I) (B6 → B6D2F1) and chronic (J-O) (BALB/c → B6) GVHD. Transgenic sgp130Fc.F1 (B6D2F1) and sgp130Fc (B6) recipients (E, J) expressed high serum levels of the IL-6 trans signaling inhibitor sgp130Fc before transplantation (n = 10-40 mice per group from 2-4 experiments).43,45 (F-H, K-M) Lethally irradiated mice received BM and T-cell grafts or TCD BM grafts as non-GVHD controls, as shown in the schema (F, K). Survival indices by Kaplan-Meier analyses (F), combined clinical scores (G), and weight loss (H) of B6D2F1 and sgp130Fc.F1 recipients after transplantation (BM and T-cell grafts, n = 18 mice per group; TCD, n = 6 mice per group; from 3 experiments). (I) Quantitative GVHD histopathological analysis of the ileum on day 7 after transplantation (n = 7 mice per group from 2 separate experiments). Survival indices by Kaplan-Meier analyses (K), combined clinical scores (L), and clinical scores (M) of skin pathology after transplantation (BM and T-cell grafts, n = 18 mice per group; TCD, n = 8-11 mice per group; from 3 experiments). (N-P) Lethally irradiated B6 and sgp130Fc mice received 10 × 106 BM and 3 × 106 T-cell grafts from BALB/c.45.1 mice, and tissue was collected 28 days (N-O) or 21 days (P) after transplantation. (N) Representative images of skin histology (200× magnification) and semiquantitative GVHD pathology analysis (O-P) of skin (O) and liver and lung (P) sections (n = 5-7 mice per group from 1 representative experiment). Data presented as mean ± standard error of the mean. *P < .05, **P < .01, ***P < .001. H&E, hematoxylin and eosin; SI, small intestine.

IL-6 trans signaling increases late after transplantation and regulates cutaneous GVHD. (A-D) Lethally irradiated B6 wild-type (B6.WT) mice received 10 × 106 BM and 5 × 106 T-cell grafts from BALB/c mice. Peripheral blood serum levels of IL-6 (A), sIL-6R (required for IL-6 trans signaling) (B), and sgp130 (antagonist of IL-6 trans signaling) (C) were analyzed from naïve B6 mice and B6 mice receiving transplants at the indicated times after transplantation (n = 6-28 mice per group from 1-4 experiments). (D) Molar ratio of sIL-6R (∼40 kDa) to sgp130 (∼100 kDa) from matched samples in panels B and C, with a higher ratio indicating a greater incidence of IL-6 trans signaling (box and Tukey whiskers). (E-O) The role of IL-6 trans signaling in GVHD was assessed in preclinical models of acute (E-I) (B6 → B6D2F1) and chronic (J-O) (BALB/c → B6) GVHD. Transgenic sgp130Fc.F1 (B6D2F1) and sgp130Fc (B6) recipients (E, J) expressed high serum levels of the IL-6 trans signaling inhibitor sgp130Fc before transplantation (n = 10-40 mice per group from 2-4 experiments).43,45  (F-H, K-M) Lethally irradiated mice received BM and T-cell grafts or TCD BM grafts as non-GVHD controls, as shown in the schema (F, K). Survival indices by Kaplan-Meier analyses (F), combined clinical scores (G), and weight loss (H) of B6D2F1 and sgp130Fc.F1 recipients after transplantation (BM and T-cell grafts, n = 18 mice per group; TCD, n = 6 mice per group; from 3 experiments). (I) Quantitative GVHD histopathological analysis of the ileum on day 7 after transplantation (n = 7 mice per group from 2 separate experiments). Survival indices by Kaplan-Meier analyses (K), combined clinical scores (L), and clinical scores (M) of skin pathology after transplantation (BM and T-cell grafts, n = 18 mice per group; TCD, n = 8-11 mice per group; from 3 experiments). (N-P) Lethally irradiated B6 and sgp130Fc mice received 10 × 106 BM and 3 × 106 T-cell grafts from BALB/c.45.1 mice, and tissue was collected 28 days (N-O) or 21 days (P) after transplantation. (N) Representative images of skin histology (200× magnification) and semiquantitative GVHD pathology analysis (O-P) of skin (O) and liver and lung (P) sections (n = 5-7 mice per group from 1 representative experiment). Data presented as mean ± standard error of the mean. *P < .05, **P < .01, ***P < .001. H&E, hematoxylin and eosin; SI, small intestine.

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