Endothelial control of IFN-gamma and i-NOS in pathogenic T cells

Yale University, New Haven CT

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Abstract

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