Graft arteriosclerosis (GA) is the major cause of late cardiac allograft failure. Although the precise pathogenesis of clinical GA is unknown, considerable evidence supports a role for IFN-gamma and for dysregulation of nitric oxide synthases (NOSs). In studies conducted during the past funding cycle using our humanized mouse model of GA, we have found that an unexpected component of NOS dysregulation involves IFN-gamma-dependent expression of inducible (i)-NOS by graft artery infiltrating T cells. The central hypothesis of this project is that the status of the endothelial cells (ECs) of an allograft artery at the time of their encounter with host effector or effector memory T cells determines whether those T cells that take up residence within the vessel wall will secrete IFN-gamma and/or express i-NOS, two characteristic features of T cells that mediate GA. In this continuation, our aims are: (1) to determine if two important innate immune signals of tissue injury, namely C5a or HMGB1, act on ECs or T cells to favor the differentiation of pathogenetic T cells that express IFN-gamma or i-NOS;(2) to identify specific EC molecules that contribute to the recruitment of pathogenetic T cells in vitro or in vivo;(3) to elucidate the control of i-NOS expression and activity in human T cells and to identify EC signals that contribute to its regulation;and (4) to determine if and how macrophages or dendritic cells (DCs) autologous to T cells influence their responses to allogeneic ECs in general and how they influence IFN-gamma or i-NOS expression in particular. These experiments will utilize both in vitro assays (co-cultures and flow chambers) and in vivo assays, including our established huPBL-SCID/bg mouse human allograft artery model of GA and two models under development, namely (i) combining adoptive transfer of human T memory cells with engraftment of human hematopoietic stem cells from the same volunteer donor in order to introduce macrophages and DCs, and (ii) transplantation of tissue-engineered synthetic human arteries containing genetically modified ECs into huPBL-SCID/bg mice in order to assess the role of specific EC molecules. Successful completion of these studies may lead to further insights into pathogenesis and to new approaches for prevention or treatment of GA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070295-09
Application #
7924680
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
9
Fiscal Year
2009
Total Cost
$442,714
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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