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

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, Pavan Reddy

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1517-1532
Number of pages16
JournalBlood Advances
Issue number19
Publication statusPublished - Aug 22 2017
Externally publishedYes

ASJC Scopus subject areas

  • Hematology


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