Pro Allograft rejection is mediated by the recipient's immunological response to donor antigen, initiated and coordinated by activated CD4+ T effector cells. However, multiple pathways operate co-incidentally in order to control and regulate the immune response, and it is proposed that this process of immunoregulation serves to both prevent and restrain T effector cell activation and the rejection reaction. DepTOR is a recently discovered cell intrinsic factor that modulates mTOR-induced signaling responses in cancer cells. Furthermore, in endothelial cells, DepTOR is potent to regulate additional intracellular signaling networks including MAPK and STAT induced responses. In preliminary studies, we have found that DepTOR is expressed at high levels in CD4+ T cells, and that forced overexpression of DepTOR modulates mitogen- induced proliferative and activation responses in vitro and in vivo. Since mTOR signaling is of critical importance for the activation of both T effectors and T regulatory cells, we suggest that these observations identify DepTOR as an important intracellular modulator with potential to dictate the phenotypic and functional outcome of an immune response. Our objectives are to develop and use novel knockout and transgenic mice to determine the mechanism of function of DepTOR in CD4+ T cells including T effectors and T regulatory cells, and to determine whether DepTOR modulates T cell activation responses and inflammation in association with allograft rejection. Our hypothesis is that DepTOR is a cell intrinsic molecule that modulates CD4+ T effector and regulatory cell function, and thus cell-mediated and alloimmune inflammation. We will test this hypothesis in two specific aims in which we will 1), determine the expression and cell intrinsic function of DepTOR in CD4+ T cells, and 2), determine the function of DepTOR in allograft rejection, and evaluate its role in regulatory alloimmune responses in vivo. Our proposed studies address fundamental but clinically relevant questions, and our approach provides for cohesiveness to translate in vitro findings into clinically relevant models in vivo. Collectively, the implications and relevance of this area of investigation is that our findings hav high potential to define DepTOR as a key modulator of immunity, and will thus indicate that it is possible to prevent or inhibit inflammation by focusing on DepTOR interactions. Since it is possible to target DepTOR degradation, this outcome will have broad clinical and therapeutic implications.
Organ transplantation is a lifesaving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. In this research proposal, we plan to determine how a recently discovered cell intrinsic regulatory protein, called DepTOR functions in the immune response, and if DepTOR modulates cellular activation and signals that are associated with rejection.
|Wedel, Johannes; Nakayama, Hironao; Kochupurakkal, Nora M et al. (2017) The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance. Curr Opin Organ Transplant 22:55-63|
|Bruneau, Sarah; Wedel, Johannes; Fakhouri, Fadi et al. (2016) Translational implications of endothelial cell dysfunction in association with chronic allograft rejection. Pediatr Nephrol 31:41-51|
|Wedel, Johannes; Bruneau, Sarah; Kochupurakkal, Nora et al. (2015) Chronic allograft rejection: a fresh look. Curr Opin Organ Transplant 20:13-20|