Research in the laboratory relates to the intragraft microvironment, and how it functions to both promote and inhibit the rejection process. Our studies focus on three broad areas including 1) immune-mediated angiogenesis and how angiogenesis factors function in the rejection process 2) how leukocyte-endothelial cell interactions and products of these interactions promote, sustain or inhibit T cell activation and allorecognition, and 3) whether persistent events within the microvasculature are associated with, or mediate chronic allograft rejection. We are currently expanding our research effort into the area of inflammation resolution, and we are specifically interested in endogenous mechanisms and regulatory signaling networks of pro-resolution. Understanding these processes will allow us to develop new paradigms for anti-rejection therapeutics following transplantation.
Active projects include:
1. Vascular Endothelial Growth Factor (VEGF)-VEGFR interactions in allograft rejection: This project is based on the observation that VEGF is overexpressed within allografts in association with ischemia-reperfusion, humoral immunity and acute and chronic rejection. Current paradigms suggest that VEGF functions as a dominant factor mediating vascular remodeling, especially in association with chronic inflammation. However, we have reported that VEGF also has potent proinflammatory effects in association with cell-mediated immune inflammation and allograft rejection. The questions in this research project relate to recent observations that the VEGF receptors (VEGFR) KDR (VEGFR2), Flt-1 (VEGFR1) and the neuropilin family molecules are expressed on populations of effector, memory and FOXP3high T regulatory cells. Our hypothesis is that intragraft VEGF interacts with circulating VEGFR-expressing T cells, and that individual VEGFRs on T cell subsets elicit signals that either promote or suppress migratory and activation responses.
2. mTOR signaling in vascular endothelial cells (EC): This research project is based on the observation that Akt-mTOR signaling is potent to mediate activation and proliferative responses in EC. However, several cell-intrinsic negative regulators of mTOR activity also function to suppress these responses in different cell types and, pharmacoloigical mTOR inhibitors are known to target the alloimmune response. We have developed in vitro and in vivo model systems to address questions about endogenous regulators of mTOR in EC, and we wish to test if they are functional to inhibit EC activation responses in vitro and to promote inflammation resolution in vivo. Our hypothesis is that augmentation of the activity of endogenous cell-intrinsic regulatory molecules sustain anti-inflammation.
3. Novel regulatory molecules in T cells: Allograft rejection is mediated by the recipient’s immunological response to donor antigen, initiated and coordinated by CD4+ T cells. Once T cells encounter alloantigen, they undergo expansion and differentiation into effectors and/or memory T cells. However, activation also results in the expansion of regulatory T cells that function to control the immune response, and it is proposed that this process of immunoregulation is critical for long-term allograft survival. Within T cells, several adapter proteins have been found to be active participants in the formation of signaling complexes, which modulate the T cell activation response. The overall goal of our research is to characterize the role and function of regulatory cell surface molecular interactions and adaptor proteins. Our hypothesis is that manipulation of these adaptors function to alter T effector-T regulatory cell interactions and transplant rejection.
4. 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 and we have performed several longitudinal analyses and have identified patterns of adhesion and activation molecules in the rejection process. Since endothelial cells are the primary target of the alloimmune response, ongoing studies are evaluating whether angiogenic profiles serve as early predictors and/or non-invasive biomarkers of the chronic rejection. We are also evaluating whether these same markers can can predict ongoing injury and/or repair in association with humoral rejection.