Engraftment of human kidney tissue in rat radiation chimera: I. A new model of human kidney allograft rejection.

Abstract

We have recently shown that lethally irradiated normal strains of mice and rats, reconstituted with bone marrow from severe combined immune deficiency (SCID) mice, can be engrafted with human peripheral blood mononuclear cells (PBMC). The feasibility of transplanting human renal tissue under the kidney capsule of the SCID/Lewis and SCID/nude radiation chimera and the effects of intraperitoneal infusion of allogeneic human PBMC on the human renal implants were investigated by histology, electron microscopy, immunohistochemistry, and fluorescence-activated cell sorter analysis. Sequential evaluation of the human renal implants from 10 days to 2 months after transplantation showed that human parenchymal elements survive in the implants up to 2 months after transplantation. The overall architecture of the transplanted kidney tissue and the normal structure of individual cells in the glomeruli and tubuli were preserved. Infusion of allogeneic human PBMC after kidney implantation resulted in patchy cellular infiltrates, composed mainly of activated human T cells, and led to prompt rejection of the human renal tissue, whereas no signs of inflammation were observed in human renal implants of chimeric rats that did not receive human PBMC. Treatment with OKT3 antibody, anti-human CD25 antibody, or CTLA4Ig fusion protein in vivo ameliorated the rejection process. Human adult kidney fragments transplanted into SCID-like rats transiently retain competent parenchymal structures. When these grafts are combined with allogeneic human PBMC, acute cellular rejection develops. We suggest that this chimeric model might be useful for the investigation of the effects of experimental manipulation on the kinetics of the inflammatory response during human renal allograft rejection.