Graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, is untreatable so that improved clinical outcomes will depend upon prevention. We have proposed that GA is caused by chronic delayed type hypersensitivity in which host T cells recognize non-self antigens presented by graft endothelial cells (ECs) and produce IFN-3, a cytokine that produces GA-like lesions in human artery segments transplanted into immunodeficient mice and that is found in clinical specimens of GA. This project will explore three approaches to reduce IFN-3 production by human memory T cells responding in vivo to transplanted allogeneic human artery segments in mouse hosts or in vitro to cultured allogeneic human ECs. First, we will subject human arterial segments to controlled hypoxia followed by reperfusion in vivo or subject cultured human endothelial cells (ECs) to hypoxia followed by reoxygenation in vitro, characterize the effect on allogeneic T cell responses, and determine if neutralization of specific vascular cell-derived mediators induced by these conditions can reduce IFN-3 production. Second, we will determine if antibodies reactive with EC antigens, especially HLA-A,B,C, alter ECs in a manner that increases allogeneic T cell responses, determine if complement activation is involved, and determine if neutralizing complement or EC-derived mediators induced by antibodies can reverse this effect. Third, we will determine conditions under which ECs induce the development or function of T regulatory cells (i-Tregs) that can reduce IFN-3 production by effector cells, characterize such i-Tregs, and develop strategies to generate such i-Tregs in vivo. In parallel, we will convert effector T cells to i-Tregs by FoxP3 protein transfection. Our hypothesis regarding the interactions of humoral and cellular immunity is novel and our creation of new humanized mouse models and our use of protein transfection to convert T effector cells to i-Treg-like cells are methodologically innovative. Successful completion of these aims may lead to new preventative therapies that target GA.

Public Health Relevance

Heart transplantation is the most effective therapy for end stage heart failure, but most heart grafts themselves eventually fail due to a peculiar form of rejection called graft arteriosclerosis (GA) that involves progressive narrowing of the arteries that nourish the heart muscle. GA cannot be effectively treated and effort has focused on prevention. This project uses novel approaches, such as humanized mice, to study how GA develops and how the T cells that cause it can be regulated, providing a firm basis for new preventative strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Fleg, Jerome
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Yale University
Schools of Medicine
New Haven
United States
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Qin, L; Li, G; Kirkiles-Smith, N et al. (2016) Complement C5 Inhibition Reduces T Cell-Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice. Am J Transplant 16:2865-2876
Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G et al. (2016) Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 1:
Abrahimi, Parwiz; Chang, William G; Kluger, Martin S et al. (2015) Efficient gene disruption in cultured primary human endothelial cells by CRISPR/Cas9. Circ Res 117:121-8
Tellides, George; Pober, Jordan S (2015) Inflammatory and immune responses in the arterial media. Circ Res 116:312-22
Jane-wit, Dan; Surovtseva, Yulia V; Qin, Lingfeng et al. (2015) Complement membrane attack complexes activate noncanonical NF-?B by forming an Akt+ NIK+ signalosome on Rab5+ endosomes. Proc Natl Acad Sci U S A 112:9686-91
Zhou, Jing; Qin, Lingfeng; Yi, Tai et al. (2015) Interferon-?-mediated allograft rejection exacerbates cardiovascular disease of hyperlipidemic murine transplant recipients. Circ Res 117:943-55
Pober, Jordan S; Jane-wit, Dan; Qin, Lingfeng et al. (2014) Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy. Arterioscler Thromb Vasc Biol 34:1609-14
Wang, Chen; Qin, Lingfeng; Manes, Thomas D et al. (2014) Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2. J Exp Med 211:395-404
Jane-Wit, Dan; Manes, Thomas D; Yi, Tai et al. (2013) Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-?B signaling in endothelial cells. Circulation 128:2504-16
Wang, Chen; Yi, Tai; Qin, Lingfeng et al. (2013) Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. J Clin Invest 123:1677-93

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