Stimulatory and inhibitory receptor interactions in xenotransplantation

Abstract

Cellular human antipig immune responses are increasingly recognized as an important barrier to successful clinical xenotransplantation. This review addresses the role of monocytes/macrophages, natural killer (NK) cells, and T cells in xenograft rejection. We focus on the receptor-ligand interactions that regulate the responses of these cells to porcine tissues and thus could be targets for immunomodulation. Activation of human monocytes by pig cells is partly due to the incapacity of porcine ligands to bind to inhibitory receptors such as signal regulatory protein alpha. Porcine UL16-binding protein 1 can functionally interact with human NK group 2D protein, thereby contributing to human NK cell activity. Transgenic pigs overexpressing human leukocyte antigen class E were generated. Cells from these pigs induced diminished NK-cell lysis, suggesting that human leukocyte antigen class E expression compensates for the inability of porcine ligands to bind to the inhibitory CD94/NK group 2A receptor on human NK cells. A new concept for the modulation of antipig T-cell reactivity may result from the finding that porcine antigen-presenting cells that overexpress human negative costimulatory PD ligands also induce diminished responses of human T cells. Disruption of stimulatory receptor-ligand interactions (e.g. by blocking antibodies or 'knockout/down' technologies) combined with transgenic overexpression of inhibitory ligands in porcine cells and tissues could be an effective approach to downregulate human antipig cellular immune responses.