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

• Published in: Blood advances Vol. 1; no. 19; pp. 1517 - 1532
• Main Authors: Toubai, Tomomi, Rossi, Corinne, Oravecz-Wilson, Katherine, Liu, Chen, Zajac, Cynthia, Wu, Shin-Rong Julia, Sun, Yaping, Fujiwara, Hideaki, Tamaki, Hiroya, Peltier, Daniel, Riwes, Mary, Henig, Israel, Brabbs, Stuart, Duckett, Colin S., Wang, Shaomeng, Reddy, Pavan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22-08-2017; American Society of Hematology; Elsevier
• Subjects: Transplantation
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2017004242

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 cIAP1−/− or XIAP−/− 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 XIAP−/− and cIAP1−/− 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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•IAP expression in hosts regulates GVHD.•IAP expression in nonhematopoietic host targets is critical for mitigating GVHD damage.