Research Summary

Dr. Briscoe's research focuses on 3 broad areas of leukocyte-endothelial cell biology. These include 1) the function of leukocyte–endothelial interactions in angiogenesis and the role of angiogenesis factors in alloimmunity; 2) how leukocyte-endothelial cell interactions promote or sustain T cell activation and allorecognition; and 3) whether persistent endothelial activation is associated with or mediates chronic allograft rejection.


1) Immune Mechanisms of Angiogenesis:
Lymphocytes and monocytes initiate angiogenesis in the process of their recruitment into allografts. We have proposed that cell surface molecules and cytokines expressed by alloactivated T cells mediate this angiogenesis reaction; and that angiogenesis factors or/and the angiogenesis reaction itself is proinflammatory. Our initial studies identified that cell surface molecule(s) expressed on T cells may stimulate the production of Vascular Endothelial Cell Growth Factor (VEGF, an established potent angiogenesis factor). We further identified that cell surface interactions among CD40L (known to be expressed on activated platelets and T cells) and its receptor CD40 (expressed on endothelial cells and monocytes) mediate the transcription of VEGF. A focus of ongoing studies is to determine the signaling pathways in CD40- dependent activation of VEGF.


2) Vascular Endothelial Growth Factor (VEGF) in Allograft Rejection:
VEGF is an established potent angiogenesis factor. However, several studies have also identified VEGF to have pro-inflammatory properties. VEGF is chemoattractant for monocytes via interactions with its receptor Flt-1 (VEGFR1). In addition, VEGF is functional in endothelial cells to promote leukocyte-endothelial cell interactions via its ability to induce endothelial cell adhesion molecule expression as well as the expression of the chemokine MCP-1. Furthermore there is evidence that VEGF may be of functional significance in alloimmunity. VEGF is expressed in cardiac, renal and in skin grafts undergoing rejection. In particular, its expression appears to be most prominent in allografts with evidence of chronic rejection. Additionally patients with genetic polymorphisms in the VEGF gene resulting in high levels of circulating VEGF have been demonstrated to be prone to develop both acute rejection and chronic rejection. Together these data suggest that VEGF is of importance in allograft rejection. Ongoing studies in the laboratory have determined that VEGF has major proinflammatory properties via its ability to regulate both adhesion molecules and chemokines. A focus of ongoing studies is to determine if VEGF functions as a proinflammatory cytokine independently of its effect on angiogenesis.


3) Post Transplant Monitoring of Humans Following Transplantation:
The laboratory has had a long-standing interest in the evaluation and monitoring of endothelial cell activation responses in allografts post transplantation. We have performed several longitudinal analyses of consecutive allografts and we identified a pattern to the expression of adhesion and activation molecules in the rejection process. We believe these findings to have clinical implications for 1) the monitoring of patients for early predictors of rejection, 2) assessment of the efficacy of immunosuppression post transplantation; and 3) for the identification of patients at high risk for the development of chronic rejection. Ongoing studies are evaluating VEGF levels post transplantation, whether angiogenic profiles serve as early predictors for the development of chronic rejection and whether circulating endothelial progenitor stem cells can predict ongoing injury and/or repair in association with humoral rejection.