IAPs protect host target tissues from graft-versus-host disease

IAPs protect host target tissues from graft-versus-host disease in mice by Tomomi Toubai, Corinne Rossi, Katherine Oravecz-Wilson, Chen Liu, Cynthia Zajac, Shin-Rong Julia Wu, Yaping Sun, Hideaki Fujiwara, Hiroya Tamaki, Daniel Peltier, Mary Riwes, Israel Henig, Stuart Brabbs, Colin S. Duckett, Shaomeng Wang, and Pavan Reddy Blood. Adv Volume 1(19): 1517 -1532 August 22, 2017 © 2017 by The American Society of Hematology

Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

AT-406 decreases the expression of XIAP in donor T cells and host nonhematopoietic target cells after allo-BMT. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

The IAP inhibitor AT-406, an SMAC mimetic, exacerbates GVHD. (A) Survival. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

IAPs are not required in donor T cells to modulate GVH responses. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

Absence of IAPs in host exacerbates GVHD in allo-BMT. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

The role of IAPs in host hematopoietic-derived APCs is dispensable for GVHD. (A-B) In vitro MLR. Isolated splenic CD 90. 2+ T cells from either syngeneic B 6 or allogeneic BALB/c animals were cultured with BMDCs derived from B 6 -WT, B 6 -c. IAP 1−/−, or B 6 -XIAP−/− animals for 96 hours (A) or with AT 406 -pretreated (1 µM; 6 hours) BMDCs derived from B 6 -WT for 96 hours (B) and analyzed for proliferation after 3 H-thymidine incorporation during the last 16 hours of incubation. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

Absence of IAPs in host target tissues plays an important role in aggravating GVHD. To make BM chimeras, B 6 -WT, B 6 -c. IAP 1−/−, and B 6 -XIAP−/− animals were lethally irradiated with 10 Gy and infused with 5 × 106 BM cells and 5 × 106 splenocytes from syngeneic B 6 Ly 5. 2 donors. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology

IAPs on host target tissues coordinately regulate gut homeostasis by distinct mechanisms in GVHD. B 6 -WT and B 6 -XIAP−/− or c. IAP 1−/− animals received 10 Gy on day − 1 and received transplants of 3 × 106 CD 90. 2+ splenic T cells along with 5 × 106 TCD-BM cells from either syngeneic B 6 or allogeneic MHC-mismatched BALB/c donors. Tomomi Toubai et al. Blood Adv 2017; 1: 1517 -1532 © 2017 by The American Society of Hematology