IN VIVO MODEL FOR HUMAN ANTI-PORCINE IMMUNE RESPONSES

Yale University, New Haven CT

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Abstract

The barriers in xenotransplantation are xenograft rejection mediated by human immune response. Porcine vascular endothelium has been shown to serve as the major cellular target in xenograft rejection. Studies of liuman immune response against xenograf( have been hampered by the lack of a suitable model in which the interaction between human T cells and porcine EC can be studied directly in vivo. Also the role of adhesion molecules, chemokines and cytokines involved in interaction between human T cells and porcine EC remains generally uncharacterized. The specific Aims are: (I). To develop porcine synthetic microvessels in vivo in SCID mice using PAEC, (2). To test the effects of over-expression of cytoprotective proteins (caspase-resistant form of Bcl-2 and telomerase), porcine adhesion molecules (E-selectin, P-selectin, ICAM-1 and VCAM), chemokines (Rantes and MCP-l), and cytokines (IFN-gamma and TNFalpha) on porcine synthetic microvessels in huPBL-SCID mice challenged with human T cells. The research design and methods will be: (I). Formation of synthetic microvessels on collagen-fibronectin gel using PAEC expressing cytoprotective proteins, porcine adhesion molecules, chemokines, or cytokines, (2). Implantation of synthetic microvessels expressing transgenes into SCID mice and challenge mice with human T cells and (3). Study the interaction between human T cells and PAEC expressing transgenes by immunochemical staining or the synthetic microvessels recovered from huPBL-SCID mice.