(503) - The Immunobiology of the Y Chromosome in Embryonic Stem Cell Transplantation for Tissue and Organ Regeneration

Abstract

The pluripotency of embryonic stem cells (ESCs) makes them a promising candidate for cell-based tissue repair strategies. However, little is known about the immune response after sex-mismatched ESC transplantation. The antigenicity of H-Y in undifferentiated ESCs was assessed. Therefore, female and male BALB/c mice received injections of 1x106 syngeneic ESCs carrying the Y chromosome. Cellular immune responses were investigated by unidirectional ELISPOT assays and confocal immunofluorescence. Longitudinal in-vivo ESC survival after transplantation was observed by teratoma assays. Female immunodeficient SCID beige and T-cell-deficient BALB/c nude mice were used as controls. Additionally, we investigated whether female BALB/c mice could acquire tolerance to ESCs carrying H-Y by immunizing them during their neonatal period according to the Medawar protocol. ELISPOT assays revealed significantly higher spot frequencies in the H-Y mismatched recipient group (see figure 1). Female BALB/c nude mice with functional NK cells but with lacking functional T cells showed only a very weak immune response indicating that the detectable immune reaction was driven by T cells rather than NK cells. The spot frequency of male BALB/c receiving male ESCs was comparable with the T cell deficient BALB/c nude group. In consistence, male BALB/c mice developed teratomas as well as the immunodeficient mice. However, no teratomas were observed in female BALB/c. When immunized with H-Y, female BALB/c developed acquired tolerance. We show for the first time that H-Y mismatched ESCs undergo immune rejection after syngeneic transplantation. Thus, the immunobiology of the y chromosome has to be considered in future efforts to develop ESC-based tissue and organ regenerative therapies.