Chronic allograft vasculopathy (CAV), or graft arterial lumen occlusion through intinna expansion, is a major cause of late heart transplant failure and patient morbidity/mortality. CAV etiology is multi-factorial, including promotion by IFN-7 secreting T helper (Th) Type-1 cells (Th1) and the migration/proliferation of smooth muscle cells (SMC) into arterial lumen. The use of rapamycin (RAPA) as an immunosuppressant is associated with reduced CAV, in part through direct inhibition of SMC, but the mechanisms by which RAPA alters the host/graft immunological environment to limit CAV are unclear. We have made the novel observation that prolonged dendritic cell (DC) exposure to RAPA confers DC resistance to pro-inflammatory stimuli by upregulating the transmembrane form of the IL-1R family member ST2 (ST2L). In addition to negatively regulating TLR and CD40 signaling, ST2L is the receptor for IL-33, a cytokine that promotes Th Type-2 (Th2) responses. IL-33 can be produced by a variety of cells, including endothelial cells (EC) and SMC, and may have cardioprotective properties. When the function of IL-33 is blocked, or ST2L is absent, pathology is exacerbated in both atherosclerosis and cardiac hypertrophy models. However, if IL-33 exhorts a Th polarization capacity through direct influence on DC, or can inhibit CAV is not known. Our central hypothesis is that IL-33 promotes DC. especially RAPA-DC expressing increased ST2L, Th2 cell polarization capacity and will prevent CAV bv both inducing Th2 skewing of T cell populations and direct cardioprotective effects on the allograft.
In AIM I, we hypothesize that IL-33 induces gene expression arid signaling pathways that mediate a DC capacity to promote Th2 response in vitro and in vivo.
In AIM II, we hypothesize that post-operative IL-33 and RAPA alone or, combined with therapeutic DC administration, leads to rejection-free heart allograft survival and prevents CAV by modulating the host immune system towards Th2 and regulatory T cell responses.
In AIM III we hypothesize that IL-33 acts via ST2L on both immune cells and cardiac allograft cells to protect cardiac allografts during acute and chronic rejection.
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 failure to prohibit CAV. We anticipate that RAPA, by increasing ST2L on DC, and IL-33 will be highly effective together to impede CAV. Mechanisms by which DC polarize Th2 responses are poorly defined and the current detailed immunological and bioinformatics studies will yield needed insights into DC immunobiology and regulation of alloimmunity.
|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