TY - JOUR
T1 - IAPs protect host target tissues from graft-versus-host disease in mice
AU - Toubai, Tomomi
AU - Rossi, Corinne
AU - Oravecz-Wilson, Katherine
AU - Liu, Chen
AU - Zajac, Cynthia
AU - Wu, Shin Rong Julia
AU - Sun, Yaping
AU - Fujiwara, Hideaki
AU - Tamaki, Hiroya
AU - Peltier, Daniel
AU - Riwes, Mary
AU - Henig, Israel
AU - Brabbs, Stuart
AU - Duckett, Colin S.
AU - Wang, Shaomeng
AU - Reddy, Pavan
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL090775 and HL128046) and National Cancer Institute (CA173878 and CA203542), an American Society of Blood and Marrow Transplantation New Investigator Award (T.T.), and a Dragon Bleu Foundation fellowship from Switzerland and Kurt and Senta Herrmann-Stiftung fellowship from Lichtenstein (C.R.).
Publisher Copyright:
© 2017 by The American Society of Hematology
PY - 2017/8/22
Y1 - 2017/8/22
N2 - Inhibitors of apoptosis proteins (IAPs) regulate apoptosis, but little is known about the role of IAPs in the regulation of immunity. Development of IAP inhibition by second mitochondria-derived activator of caspase (SMAC) mimetics is emerging as a novel therapeutic strategy to treat malignancies. We explored the role of IAPs in allogeneic immunity with 2 distinct yet complementary strategies, namely, chemical and genetic approaches, in clinically relevant models of experimental bone marrow transplantation (BMT). The small-molecule pan-IAP inhibitor SMAC mimetic AT-406 aggravated gastrointestinal graft-versus-host disease (GVHD) in multiple models. The role of specific IAPs in various host and donor cellular compartments was explored by utilizing X-linked IAP (XIAP)- and cellular IAP (cIAP)-deficient animals as donors or recipients. Donor T cells from C57BL/6 cIAP12/2 or XIAP2/2 animals demonstrated equivalent GVHD severity and allogeneic responses, both in vivo and in vitro, when compared with B6 wild-type (B6-WT) T cells. By contrast, when used as recipient animals, both XIAP2/2 and cIAP12/2 animals demonstrated increased mortality from GVHD when compared with B6-WT animals. BM chimera studies revealed that cIAP and XIAP deficiency in host nonhematopoietic target cells, but not in host hematopoietic-derived cells, is critical for exacerbation of GVHD. Intestinal epithelial cells from IAP-deficient animals showed reduced levels of antiapoptotic proteins as well as autophagy-related protein LC3 after allogeneic BMT. Collectively, our data highlight a novel immune cell-independent but target tissue-intrinsic role for IAPs in the regulation of gastrointestinal damage from GVHD.
AB - Inhibitors of apoptosis proteins (IAPs) regulate apoptosis, but little is known about the role of IAPs in the regulation of immunity. Development of IAP inhibition by second mitochondria-derived activator of caspase (SMAC) mimetics is emerging as a novel therapeutic strategy to treat malignancies. We explored the role of IAPs in allogeneic immunity with 2 distinct yet complementary strategies, namely, chemical and genetic approaches, in clinically relevant models of experimental bone marrow transplantation (BMT). The small-molecule pan-IAP inhibitor SMAC mimetic AT-406 aggravated gastrointestinal graft-versus-host disease (GVHD) in multiple models. The role of specific IAPs in various host and donor cellular compartments was explored by utilizing X-linked IAP (XIAP)- and cellular IAP (cIAP)-deficient animals as donors or recipients. Donor T cells from C57BL/6 cIAP12/2 or XIAP2/2 animals demonstrated equivalent GVHD severity and allogeneic responses, both in vivo and in vitro, when compared with B6 wild-type (B6-WT) T cells. By contrast, when used as recipient animals, both XIAP2/2 and cIAP12/2 animals demonstrated increased mortality from GVHD when compared with B6-WT animals. BM chimera studies revealed that cIAP and XIAP deficiency in host nonhematopoietic target cells, but not in host hematopoietic-derived cells, is critical for exacerbation of GVHD. Intestinal epithelial cells from IAP-deficient animals showed reduced levels of antiapoptotic proteins as well as autophagy-related protein LC3 after allogeneic BMT. Collectively, our data highlight a novel immune cell-independent but target tissue-intrinsic role for IAPs in the regulation of gastrointestinal damage from GVHD.
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U2 - 10.1182/bloodadvances.2017004242
DO - 10.1182/bloodadvances.2017004242
M3 - Article
AN - SCOPUS:85059551638
VL - 1
SP - 1517
EP - 1532
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 19
ER -