Research Interests

Studies of human T cell recognition of human and porcine endothelial cells focus on both direct and indirect recognition of MHC, constitutive and inducible adhesion molecules and costimulatory pathways. Analysis of in vitro function will be complemented by studies of in vivo model systems using synthetic microvessels, vessel and skin grafts into humanized SCID mice to study lymphocyte recruitment, vascular remodeling and to evaluate allo and xenograft interactions. One major goal of this system is to evaluate the potential of porcine cells as a source of donor cells for xenografts. We also hope to extend this model to develop conditions to enhance the survival and function of transplanted human islets via revascularization.

We have shown that human Bcl-2 overexpression in human or porcine endothelial cells confers many anti-apoptotic properties and enhances vascular remodeling but only human EC (HUVEC) and not porcine endothelial cells (PAEC) are protected from human CTL in vitro. We have shown that Bcl-2 overexpression confers essentially complete cytoprotection of HUVEC but not PAEC in vivo. We have used peripheral blood mononuclear cells (PBMC) or human CTL lines raised against the EC used in the microvessels. The in vivo models are now well developed and can be utilized to assess the function of genes expressed in endothelial cells essentially at will. Surprisingly, the anti-porcine response using PBMC in the SCID mouse models is almost insignificant whereas there is a significant anti-human response. Injection of TNF rapidly activates a potent anti-porcine response. Our current efforts are aimed at assessing the role of selectins, ICAMs as well as other molecules in the apparent block to a xeno response. One candidate is a protein secreted specifically from EC designated ESM-1/endocan which is a ligand for human LFA-1.

Separate experiments will address recognition, activation and signaling in murine lymphocytes. Ly-6 antigens are characteristically tethered to the membrane via GPI anchors and as such would be characteristically located in lipid rafts. The role of Ly-6 antigens in regulating the protein components of lipid rafts is under investigation. Studies of Pax5 knockout mice that accumulate proB progenitor populations will be used to evaluate the role of Ly-6 antigens on hematopoietic differentiation as well as on bone cell development (osteoclasts and osteoblasts). Results using Ly-6A knockout mice suggests that Ly-6A is required for the generation of Treg cells. The role of regulatory T cells in prevention of EAE is also under investigation.