- Prof. Bruce Reitz, Principal Investigator
- Dr. Dominic C. Borie, Co-Investigator
- Stanford University School of Medicine, Stanford, USA
- Can Blockade of Signals in Vascular Cells Prevent Chronic Rejection of Transplants?
Inhibition of the Janus Kinase (JAK) 3 with tyrosine kinase inhibitors is emerging as a new modality of immunosuppression to effectively prevent organ allograft rejection. Although participation of the JAK/signal transduction and activator of transcription (STAT) pathway has been reported in endothelial cells (ECs) activated by a variety of stimuli, its role, and more precisely that of JAK3, in the context of allotransplantation and immunosuppression has not been studied. ECs are key players in the onset of chronic allograft vasculopathy (CAV), a condition characterized by neointimal myoproliferation in response to EC activation, and that plagues organ transplantation. As ECs of organ transplant recipients treated with JAK3 inhibitors will be exposed to the effects of those immunosuppressive molecules, we are curious to characterize the presence and activation profile of JAK3 in ECs in response to allo-immune stimuli represented by allo-antibodies and cytokines that participate in provoking allograft rejection and also by hyperimmune serum. We will subsequently study how JAK3 blockade via pharmacological inhibition, monoclonal antibodies, and RNA interference in cultured ECs affects those cells activation and/or proliferation upon subsequent stimulation. Finally, we will test our hypothesis that grafts and vessels devoid from JAK3 expression (JAK3-/-) are less prone to CAV by performing aortic transplants using vessels harvested from donors (allo-immune injury) and by creating catheter-induced endothelial injury (mechanical injury) in JAK3-/- animals. Altogether, this research proposal will provide original insights on the participation of JAK3 in allo-stimulated ECs and will provide critical knowledge of the effects of JAK3 inhibiting strategies on EC function and on the development of CAV.