Recipient IL-33 Promotes Type 1 Alloimmunity and Lethal Acute GVHD Following alloHCT
B. Matta,1 D. Reichenbach,2 V. Schwarze,3 V. Tkachev,4 L. Mathews,1 Q. Liu,1 M. Warncke,5 J. Ferrara,4 R. Zeiser,3 B. Blazar,2 H. Turnquist.1
1Surgery, Univ. of Pittsburgh, Pittsburgh, PA 2Pediatrics, Univ. of Minnesota, Minneapolis, MN 3Hematology and Oncology, Univ. Medical Center Freiburg, Freiburg, Germany 4Pediatrics, Univ. of Michigan, Ann Arbor, MI 5Novartis Institute for Biomedical Research, Basel, Switzerland.
Background: Graft-versus-host disease (GVHD) is a common complication of allogeneic (allo) hematopoietic cell transplantation (HCT) that limits its widespread application for the induction of transplant tolerance. Recipient conditioning before alloHCT involves irradiation, which causes significant damage to the lung and gut epithelium. These same tissues are primary targets of the alloimmune responses mediating GVHD. IL-33 is a cytokine expressed by epithelial cells and able to support Type 1, Type 2, and regulatory immune responses. As it was unknown, we defined if IL-33 impacts GVHD pathogenesis following alloHCT.
Methods: Recipient mice received a lethal dose of total body irradiation (TBI) followed by administration of allo T cell-depleted bone marrow (BM) alone or with allo splenic T cells. Where indicated, recipient mice, donor BM or T cells were deficient for IL-33 or its receptor, ST2. Recipient survival, weight, and clinical score were monitored. Tissues and serum were harvested for IL-33 quantitation and analysis of alloimmune responses.
Results: IL-33 expression is increased rapidly in CD45- cells of the small intestine after TBI. This expression is sustained at least through day 14 in alloHCT recipient mice. Recipients deficient for IL-33 exhibit protection from GVHD. Wild type recipients of il33-/- donor BM or T cells, however, developed unabated GVHD. Blockade of IL-33 signaling using the antagonist ST2-Fc also prevented GVHD and reduced Type 1-dominated alloimmune responses. Conversely, IL-33 administered post-alloHCT accelerates GVHD lethality. Development of GVHD after alloHCT depended on ST2 expression by donor T cells.
Conclusions: Recipient IL-33 expression, elevated by TBI and alloHCT, drives donor T cell Type 1 alloimmunity to promote acute GVHD lethality. These findings are the first to reveal an IL-33-mediated pathway supporting Type 1 alloimmunity. These data also establish the IL-33/ST2 axis as a targetable pathway to lessen the risk of GVHD and thus broaden the use of alloHCT for tolerance-induction protocols.