- Dr Michael Autieri, Principal Investigator
- Ms Sheri Kelemen, Technician
- Temple University School of Medicine, Philadelphia, USA
- The Role of Allograft-Inflammatory Factor-1 in Development of Graft Vascular Disease
Despite advances in organ preservation and immunosuppressive drugs, the vascular narrowing indicative of graft vascular disease (CATV) is the major complication that limits long-term survival of cardiac transplantation. Characteristic cellular changes that typify CATV are activation of vascular smooth muscle cells (VSMC), causing them to migrate from the artery wall to the lumen of the vessel where they proliferate. This is responsible for loss in lumen diameter and organ failure. Recruitment of stem cells to the transplanted organ has also been shown to contribute to this process. The risk of infection and malignancy associated with immunosuppressive therapy support the need to identify a molecular target which directly impacts the VSMC response to injury, rather than suppress the immune response. In the past several years, we have shown that expression of a protein termed allograft inflammatory factor-1 (AIF-1) causes VSMC activation, and is strongly associated with development of clinical CATV. AIF-1 expression also causes granulocyte-colony stimulating factor (G-CSF) expression, which is a migration factor for stem cells and inflammatory cells. VSMC which express AIF-1 are chemotactic for stem cells and monocytes.
We have recently developed a transgenic mouse in which over-expression of AIF-1 is limited to large and medium sized arteries. This mouse represents a novel opportunity to investigate the role of this important protein in development of CATV. We will perform heart transplants into mice, and compare the development of CATV in the AIF-1 transgenic hearts versus the wild-type mouse hearts. We will compare lumen size, and expression of proliferative and inflammatory genes in these hearts. We will also identify and compare the amount of stem cells and inflammatory cells recruited to the arteries in these hearts. Characterization of AIF-1 function will increase our understanding of allograft-induced VSMC activation, of vascular-immune cell cross talk, and stem cell recruitment.