Abstract
Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation in mice reveals the earliest gestational time point at which kidney precursor cells, of both human and pig origin, differentiate into functional nephrons and not into other, non-renal professional cell types. Moreover, successful organogenesis is achieved when using the early kidney precursors, but not later-gestation kidneys. The formed, miniature kidneys are functional as evidenced by the dilute urine they produce. In addition, decreased immunogenicity of the transplants of early human and pig kidney precursors compared with adult kidney transplants is demonstrated in vivo. Our data pinpoint a window of human and pig kidney organogenesis that may be optimal for transplantation in humans.
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References
Woolf, A.S. in Pediatric Nephrology 4th edn. (eds. Barratt, T.M., Avner, A. & Harmon, W.) 1–19 (Williams & Wilkins, Baltimore, Maryland, 1999).
Rogers, S.A., Lowell, J.A., Hammerman, N.A. & Hammerman, M.R. Transplantation of developing metanephroi into adult rats. Kidney Int. 54, 27–37 (1998).
Rogers, S.A., Liapis, H. & Hammerman, M.R. Transplantation of metanephroi across the major histocompatibility complex in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R132–136 (2001).
Rogers, S.A. & Hammerman, M.R. Transplantation of rat metanephroi into mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1865–1869 (2001).
Rogers, S.A. & Hammerman, M.R. Transplantation of metanephroi after preservation in vitro. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R661–665 (2001).
Auchincloss, H. & Sachs, D.H. Xenogeneic transplantation. Annu. Rev. Immunol. 16, 433–470 (1998).
Hammerman, M.R. Xenotransplantation of renal primordia. Curr. Opin. Nephrol. Hypertens. 11, 11–16 (2002).
Dekel, B. et al. Engraftment of human kidney tissue in rat radiation chimera: II. Human fetal kidneys display reduced immunogenicity to adoptively transferred human PBMC and exhibit rapid growth and development. Transplantation 64, 1550–1558 (1997).
Dekel, B. et al. In vivo modulation of the allogeneic immune response by human fetal kidneys: the role of cytokines, chemokines, and cytolytic effector molecules. Transplantation 69, 1470–1478 (2000).
Oliver, J.A., Barasch, J., Yang, J., Herzlinger, D. & Al-Awqati, Q. Metanephric mesenchyme contains embryonic renal stem cells. Am. J. Physiol. Renal Physiol. 283, F799–809 (2002).
Gritsch, H.A. et al. The importance of nonimmune factors in reconstitution by discordant xenogeneic hematopoietic cells. Transplantation 57, 906–917 (1994).
Cascalho, M. & Platt, J.L. The immunological barrier to xenotransplantation. Immunity 14, 437–446 (2001).
Vermeulen, P.B. et al. Quantification of angiogenesis in solid human tumours: An international consensus on the methodology and criteria of evaluation. Eur. J. Cancer 32A, 2474–2484 (1996).
Dekel, B. et al. Engraftment of human kidney tissue in rat radiation chimera: I. A new model of human kidney allograft rejection. Transplantation 64, 1541–1550 (1997).
Dekel, B. et al. Acute cellular rejection of human renal tissue by adoptive transfer of allogeneic human peripheral blood mononuclear cells into chimeric rats: sequential gene expression of cytokines, chemokines and cytolytic effector molecules, and their regulation by CTLA-4-Ig. Int. Immunol. 11, 1673–1683 (1999).
Boussiotis, V.A. et al. Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation. J. Exp. Med. 184, 365–376 (1996).
Schwartz, R.H. Models of T cell anergy: Is there a common molecular mechanism? J. Exp. Med. 184, 1–8 (1996).
Sayegh, M.H. & Turka, L.A. The role of T-cell costimulatory activation pathways in transplant rejection. N. Engl. J. Med. 338, 1813–1821 (1998).
Li, Y. et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nature Med. 5, 1298–1302 (1999).
Linsley, P.S. et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174, 561–569 (1991).
Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95, 14863–14868 (1998).
Zuo, F. et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc. Natl. Acad. Sci. USA 99, 6292–6297 (2002).
Medawar, P.B. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7, 320–323 (1953).
Nelson, P.J. & Krensky, A.M. Chemokines, chemokine receptors, and allograft rejection. Immunity 14, 377–386 (2001).
Tedder, T.F., Steeber, D.A., Chen, A. & Engel, P. The selectins: vascular adhesion molecules. FASEB J. 9, 866–873 (1995).
O'Regan, A.W., Nau, G.J., Chupp, G.L. & Berman, J.S. Osteopontin (Eta-1) in cell-mediated immunity: Teaching an old dog new tricks. Immunol. Today 21, 475–478 (2000).
Ashkar, S. et al. Eta-1 (osteopontin): An early component of type-1 (cell-mediated) immunity. Science 287, 860–863 (2000).
Xie, Y. et al. Expression, roles, receptors, and regulation of osteopontin in the kidney. Kidney Int. 60, 1645–1657 (2001).
Pratt, J.R., Basheer, S.A. & Sacks, S.H. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nature Med. 8, 582–587 (2002).
Segall, H., Lubin, I., Marcus, H., Canaan, A. & Reisner, Y. Generation of primary antigen-specific human cytotoxic T lymphocytes in human/mouse radiation chimera. Blood 88, 721–730 (1996).
Reisner, Y. & Dagan, S. The Trimera mouse: generating human monoclonal antibodies and an animal model for human diseases. Trends Biotechnol. 16, 242–246 (1998).
Kreisel, D. et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: An alternative mechanism of allorecognition. Nature Med. 8, 233–239 (2002).
Briscoe, D.M. et al. The allogeneic response to cultured human skin equivalent in the hu-PBL-SCID mouse model of skin rejection. Transplantation 67, 1590–1599 (1999).
Benichou, G., Valujskikh, A. & Heeger, P.S. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J. Immunol. 162, 352–358 (1999).
Woolf, A.S., Palmer, S.J., Snow, M.L. & Fine, L.G. Creation of a functioning chimeric mammalian kidney. Kidney Int. 38, 991–997 (1990).
Kaminski, N. et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc. Natl. Acad. Sci. USA 97, 1778–1783 (2000).
Kaminski, N. & Friedman, N. Practical approaches to analyzing results of microarray experiments. Am. J. Respir. Cell Mol. Biol. 27, 125–132 (2002).
Acknowledgements
Supported in part by a grant from Mrs. E. Drake and the Gabriella Rich Center for Transplantation Biology Research and the Edward H. Kass Award from the American Physicians Fellowship (B.D.). Y.R. holds the Henry H. Drake Professorial Chair in Immunology.
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Y.R. is a member of the Scientific Advisory Board and a shareholder of XTL Biopharmaceuticals, Ltd., Ness Ziona, Israel, which has an exclusive license from the Weizmann Institute of Science for the “Trimera” (human/mouse chimera) technology. However, this study was not funded by the company.
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Dekel, B., Burakova, T., Arditti, F. et al. Human and porcine early kidney precursors as a new source for transplantation. Nat Med 9, 53–60 (2003). https://doi.org/10.1038/nm812
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DOI: https://doi.org/10.1038/nm812
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