Stimulatory and inhibitory receptor interactions in xenotransplantation

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.