Chronic allograft vasculopathy (CAV), or graft arterial lumen occlusion through intima expansion, is a major cause of late heart transplant failure and patient morbidity/mortality. The etiology of CAV is multi-factonal, but involves promotion by IFN-y secreting T helper (Th) Type-1 cells. IL-33 and its receptor, ST2 are associated with the promotion of Type-2 (Th2) responses that have been proposed to support allograft survival. We find that IL-33 administration prolongs survival of fully-MHC mismatched, mouse heterotopic heart allografts. However, we demonstrate that IL-33, in addition to supporting Th2 responses, is a facilitator of myeloid antigen presenting cells (APC), which increase regulatory T cells (Treg), potent immunosuppressive cells directly implicated in tolerance. Specifically, we demonstrate that IL-33 administration increases both immature myeloid DC (mDC) and myeloid-derived suppressor cells (MDSC) that display the capacity to increase Treg during their interaction with allogeneic CD4+ T cell populations. None-the-less, we also find that ST2 is highly upregulated in rejecting allografts where, with IL-33, it may inhibit activation of cardiac endothelial cells (EC). In total, our findings support the capacity of IL-33, acting through ST2 on immune and cardiac cells, to facilitate allograft survival and potentially limit CAV. Our central and unifying hypothesis is that following heart transplantation, IL-33 promotes allograft survival by both generating myeloid APC that mediate Th2 cell polarization and Treg expansion, as well as through the direct protective effects on ST2 expressing cells ofthe allograft.
In AIM I, we will determine how specific IL-33-induced genes and signaling pathways mediate the capacity of IL-33-exposed mDC to promote Th2 response and Treg in vitro and in vivo.
In AIM II, we will determine the mechanisms by which IL-33-expanded immunoregulatory myeloid cells, including mDC and MDSC, facilitate allograft survival.
In AIM III, we will dissect immune versus non-immune contributions to the cardiac protective capacity of ST2 and IL-33 in acute and chronic allograft rejection.

Public Health Relevance

. Transplantation is the only therapeutic option for end-stage heart disease. Immunosuppressants have improved short-, but not long-term allograft survival, due in large part to a failure to prohibit allograft vasculopathy. We expect that IL-33, by expanding potent regulatory immune cells and direct protection of the allograft, will be demonstrated an important biological for improving cardiac transplant outcomes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
4R00HL097155-03
Application #
8307148
Study Section
Special Emphasis Panel (NSS)
Program Officer
Roltsch, Mark
Project Start
2011-08-22
Project End
2014-07-31
Budget Start
2011-08-22
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$249,000
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Matta, Benjamin M; Turnquist, H?th R (2016) Expansion of Regulatory T Cells In Vitro and In Vivo by IL-33. Methods Mol Biol 1371:29-41
Mathews, L R; Lott, J M; Isse, K et al. (2016) Elevated ST2 Distinguishes Incidences of Pediatric Heart and Small Bowel Transplant Rejection. Am J Transplant 16:938-50
Liu, Quan; Turnquist, Heth R (2016) Controlling the burn and fueling the fire: defining the role for the alarmin interleukin-33 in alloimmunity. Curr Opin Organ Transplant 21:45-52
Matta, Benjamin M; Reichenbach, Dawn K; Zhang, Xiaoli et al. (2016) Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood 128:427-39
Gao, Xin; Wang, Xuefeng; Yang, Qianting et al. (2015) Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J Immunol 194:438-45
Reichenbach, Dawn K; Schwarze, Vincent; Matta, Benjamin M et al. (2015) The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. Blood 125:3183-92
Raïch-Regué, Dàlia; Rosborough, Brian R; Watson, Alicia R et al. (2015) mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo. J Immunol 194:4767-76
Turner, Michael S; Isse, Kumiko; Fischer, Douglas K et al. (2014) Low TCR signal strength induces combined expansion of Th2 and regulatory T cell populations that protect mice from the development of type 1 diabetes. Diabetologia 57:1428-36
Stenger, Elizabeth O; Rosborough, Brian R; Mathews, Lisa R et al. (2014) IL-12hi rapamycin-conditioned dendritic cells mediate IFN-?-dependent apoptosis of alloreactive CD4+ T cells in vitro and reduce lethal graft-versus-host disease. Biol Blood Marrow Transplant 20:192-201
Rosborough, B R; Raïch-Regué, D; Liu, Q et al. (2014) Adenosine triphosphate-competitive mTOR inhibitors: a new class of immunosuppressive agents that inhibit allograft rejection. Am J Transplant 14:2173-80

Showing the most recent 10 out of 23 publications