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Accommodation of vascularized xenografts: Expression of “protective genes” by donor endothelial cells in a host Th2 cytokine environment

Nature Medicine volume 3, pages 196–204 (1997)Cite this article

Abstract

Organ xenografts under certain circumstances survive in the presence of anti-graft antibodies and complement, a situation referred to as “accommodation.” We find that the endothelial cells (ECs) in hamster hearts that accommodate themselves in rats express genes, such as A20 and bcl-2, that in vitro protect ECs from apoptosis and prevent upregulation in those cells of proinflammatory genes such as cytokines, procoagulant and adhesion molecules. Hearts that are rejected do not express these genes. In addition, vessels of rejected hearts show florid transplant arteriosclerosis whereas those of accommodated hearts do not. Accommodated xenografts have an ongoing T helper cell type 2 (Th2) cytokine immune response, whereas the rejected grafts have a Th1 response. We propose a model for factors that contribute to the survival of xenografts and the avoidance of transplant arteriosclerosis.

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References

  1. Slapak, M., Digard, N., Ahmed, M., Shell, T. & Thompson, F. Renal transplantation across the ABO barrier — A 9-year experience. Transplant.Proc. 22, 1425–1428 (1990).

    CAS  PubMed  Google Scholar 

  2. Alexandre, G.P.J., Latinne, D., Gianello, P. & Squifflet, J.P. Preformed cytotoxic antibodies and ABO-incompatible grafts. Clin. Transplant. 5, 583–587 (1991).

    Google Scholar 

  3. Bach, F.H., Turman, M.A., Varcellotti, G.M., Platt, J.L. & Dalmasso, A.P. Accommodation: A working paradigm for progressing towards clinical discordant xenografting. Transplant. Proc. 23, 205–208 (1991).

    CAS  Google Scholar 

  4. Winkler, H., Ferran, C. & Bach, F.H. Accommodation of xenografts: A concept revisited. Xenotransplantation 2, 53–56 (1995).

    Article  Google Scholar 

  5. Blakely, M.L. et al. Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection. Transplantation 58, 1059–1066 (1994).

    Article  CAS  Google Scholar 

  6. Lesnikoski, B.A., Shaffer, D.A., Van der Werf, W.J., Hancock, W.W. & Bach, F.H. Endothelial and host mononuclear cell activation and cytokine expression during rejection of pig-to-baboon discordant xenografts. Transplant. Proc. 27, 290–291 (1995).

    CAS  PubMed  Google Scholar 

  7. Opipari, A.J., Hu, H.M., Yabkowitz, R. & Dixit, V.M. The A20 zinc finger protein protects Cells from TNF cytotoxicity. J. Biol. Chem. 267, 12424–12427 (1992).

    CAS  PubMed  Google Scholar 

  8. Tsujimoto, Y. & Croce, C.M. Analysis of the structure, transcripts and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl. Acad.Sci.USA 83, 5214–5218 (1986).

    Article  CAS  Google Scholar 

  9. Boise, L.H. et al. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).

    Article  CAS  Google Scholar 

  10. Jaattela, M., Mouritzen, H., Elling, F. & Bastholm, L. A20 zinc finger protein inhibits TNF and IL-1 signaling. J. Immunol. 156, 1166–1173 (1996).

    CAS  PubMed  Google Scholar 

  11. Cooper, J.T. et al. A20 blocks endothelial cell activation through a NF-kappa B-dependent mechanism. J. Biol. Chem. 271, 18068–18073 (1996).

    Article  CAS  Google Scholar 

  12. Song, H.Y., Rothe, M. & Goeddel, D.V. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappa B activation. Proc. Natl. Acad. Sci. USA 93, 6721–6725 (1996).

    Article  CAS  Google Scholar 

  13. Read, M.A., Whitley, M.Z., Williams, A.J. & Collins, T. NF-κB and IκBα — An inducible regulatory system in endothelial activation. J. Exp. Med. 179, 503–512 (1994).

    Article  CAS  Google Scholar 

  14. Ferran, C. et al. Inhibition of NF-kappa B by pyrrolidine dithiocarbamate blocks endothelial cell activation. Biochem. Biophys. Res. Commun. 214, 212–223 (1995).

    Article  CAS  Google Scholar 

  15. Wrighton, C.J. et al. Inhibition of endothelial Cell activation by adenovirus-mediated expression of IκBα, an inhibitor of the transcription factor NF-κB. J. Exp. Med. 183, 1013–1022 (1996).

    Article  CAS  Google Scholar 

  16. Bach, F.H. et al. Barriers to xenotransplantation. Nature Med. 1, 869–873 (1995).

    Article  CAS  Google Scholar 

  17. Arthur, R.P. & Mason, D.T. Cells that help B cell responses to soluble antigen are distinguishable from those producing interleukin-2 on mitogenic or allogeneic stimulation. J. Exp. Med, 163, 774–786 (1986).

    Article  CAS  Google Scholar 

  18. Papp, I. et al. Evidence for functional heterogeneity of rat CD4+ T cells in vivo — Differential expression of IL-2 and IL-4 messenger RNA in recipients of cardiac allografts. J. Immunol. 148, 1308–1314 (1992).

    CAS  PubMed  Google Scholar 

  19. Hancock, W.W., Sayegh, M.H., Kwok, C.A., Weiner, H.L. & Carpenter, C.B. Oral but not intravenous alloantigen prevents accelerated allograft rejection by selective intragraft Th2 Cell activation. Transplantation 55, 1112–1118 (1993).

    Article  CAS  Google Scholar 

  20. Hasan, R., Vandenbogaerde, J.B., Wallwork, J. & White, D.J.G. Evidence that long-term survival of concordant xenografts is achieved by inhibition of antispecies antibody production. Transplantation 54, 408–413 (1992).

    Article  CAS  Google Scholar 

  21. Takeuchi, T., Lowry, R.P. & Konieczny, B. Heart allografts in murine systems — The differential activation of Th2-like effector cells in peripheral tolerance. Transplantation 53, 1281–1294 (1992).

    Article  CAS  Google Scholar 

  22. Ferraresso, M., Tian, L., Ghobrial, R., Stepkowski, S.M. & Kahan, B.D. Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats. J. Immunol. 153, 3307–3318 (1994).

    CAS  PubMed  Google Scholar 

  23. Sayegh, M.H. et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J. Exp. Med. 181, 1869–1874 (1995).

    Article  CAS  Google Scholar 

  24. Hancock, W.W. et al. Blocking of mononuclear cell accumulation, cytokine production and endothelial activation within rat cardiac allografts by CD4 monoclonal antibody therapy. Transplantation 53, 1276–1280 (1992).

    Article  CAS  Google Scholar 

  25. Kupiec-Weglinski, J.W. et al. CD4 mAb therapy modulates alloantibody production and intracardiac graft deposition in association with selective inhibition of Th1 lymphokines. J. Immunol. 151, 5053–5061 (1993).

    CAS  PubMed  Google Scholar 

  26. Mottram, P.L., Han, W.R., Purcell, L.J., McKenzie, I.F.C. & Hancock, W.W. Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and IFN-γ in long-surviving mouse heart allografts after brief CD4 monoclonal antibody therapy. Transplantation 59, 559–565 (1995).

    Article  CAS  Google Scholar 

  27. Geng, Y., Gulbins, E., Altman, A. & Lotz, M. Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the ras signaling pathway. Proc. Natl. Acad. Sci. USA 91, 8602–8606 (1994).

    Article  CAS  Google Scholar 

  28. Naume, B. & Espevik, T., Review : Immunoregulatory effects of cytokines on natural killer cells. Scand. J. Immunol. 40, 128–134 (1994).

    Article  CAS  Google Scholar 

  29. Hancock, W.W. Chemokines and the pathogenesis of T cell-dependent immune responses. Am. J. Pathol. 148, 681–684 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. de Martin, R. et al. Cytokine-inducible expression in endothelial Cells of an IκBα-like gene is regulated by NF-κB. EMBOJ. 12, 2773–2779 (1993).

    Article  CAS  Google Scholar 

  31. Bellas, R.E., Lee, J.S. & Sonenshein, G.E. Expression of a constitutive NF-κB-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells. J. Clin. Invest. 96, 2521–2527 (1995).

    Article  CAS  Google Scholar 

  32. Juckett, M.B. et al. Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. Am. J. Pathol. 147, 782–789 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Vanhove, B., de Martin, R., Lipp, J. & Bach, F. H. Human xenoreactive antibodies of the IgM isotype activate pig endothelial cells. Xenotransplantation 1, 17–23 (1994).

    Article  Google Scholar 

  34. Dalmasso, A.P., He, T. & Benson, B. A. Human IgM xenoreactive natural antibodies can induce resistance of porcine endothelial cells to complement-mediated injury. Xenotransplantation 3, 54–62 (1996).

    Article  Google Scholar 

  35. Agarwal, A., Kim, Y., Matas, A.J., Alam, J. & Nath, K.A. Gas-generating systems in acute renal allograft rejection in the rat — Co-induction of heme oxygenase and nitric oxide synthase. Transplantation 61, 93–98 (1996).

    Article  CAS  Google Scholar 

  36. Willis, D., Moore, A.R., Frederick, R. & Willoughby, D. A. Heme oxygenase: A novel target for immunomodulation of the inflammatory response. Nature. Med. 2, 87–90 (1996).

    Article  CAS  Google Scholar 

  37. Hockenbery, D.M., Oltvai, Z.N., Yin, X.M., Milliman, C. & Korsmeyer, S.J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75, 241 –51 (1993).

    Article  CAS  Google Scholar 

  38. Vaux, D.L. & Strasser, A. The molecular biology of apoptosis. Proc. Natl. Acad. Sci. USA 93, 2239–2244 (1996).

    Article  CAS  Google Scholar 

  39. Jaattela, M., Mouritzen, H., Elling, F. & Bastholm, L. A20 zinc finger protein inhibits TNF and IL-1 signaling. J. Immunol. 156, 1166–1173 (1996).

    CAS  PubMed  Google Scholar 

  40. Grimm, S., Bauer, K.A., Baeuerle, P.A. & Schulze-Osthoff, K. Bcl-2 down-regulates the activity of transcription factor NF-κB induced upon apoptosis. J. Cell. Biol. 134, 13–23 (1996).

    Article  CAS  Google Scholar 

  41. Geng, Y.G., Wu, Q., Muszynski, M., Hansson, G.K. & Libby, P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with IFN-γ, TNF-α, and IL-1β. Arterioscler. Thromb. Vasc. Biol. 16, 19–27 (1996).

    Article  CAS  Google Scholar 

  42. Bennett, M.R., Evan, G.I. & Schwartz, S. M. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J. Clin. Invest. 95, 2266–2271 (1995).

    Article  CAS  Google Scholar 

  43. Shaddy, R. et al. Myocardial apoptosis in a heterotopic murine heart transplant model of chronic rejection and graft vasculopathy. J. Heart Lung Transplant. 15, S97 (1996).

    Google Scholar 

  44. Autieri, M.V., Yue, T.L., Ferstein, G.Z. & Ohlstein, E. Antisense oligonucleotides to the p65 subunit of NFkB inhibit vascular smooth muscle cell adherence and proliferation and prevent neointima formation in rat carotid arteries. Biochem. Biophys. Res. Commun. 213, 827–836 (1995).

    Article  CAS  Google Scholar 

  45. He, X.W., Zhong, W.Y., Goronzy, J.J. & Weyand, C.M. Induction of B Cell apoptosis by Th0, but not Th2, CD4+ T Cells. J. Clin. Invest. 95, 564–571 (1995).

    Article  CAS  Google Scholar 

  46. Platt, J.L. et al. Release of heparan sulphate from endothelial cells: Implications for pathogenesis of hyperacute rejection. J. Exp. Med. 171, 1363–1368 (1990).

    Article  CAS  Google Scholar 

  47. Tsuchida, A., Salem, H., Thomson, N.M. & Hancock, W.W. Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression. J. Exp. Med. 175, 81–90 (1992).

    Article  CAS  Google Scholar 

  48. Robson, S.C. et al. Potential mechanism of abnormal thromboregulation in xenograft rejection: Loss of ecto-ATPases upon endothelial Cell activation. Transplant. Proc. 28, 536 (1996).

  49. Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline responsive promoters. Proc. Natl. Acad. Sci.USA 89, 5547–5551 (1992).

    Article  CAS  Google Scholar 

  50. Ono, K. & Lindsey, E. S. Improved technique of heart transplantation in rats. J. Thorac. Cardiovasc. Surg. 57, 225–229 (1969).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sandoz Center for Immunobiology, Department of Surgery, New England Deaconess Hospital and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts, 02215, USA

    Fritz H. Bach, Christiane Ferran, Paul Hechenleitner, Walter Mark, Hans Winkler, Anne Badrichant, Daniel Candinas & Waune W. Hancock

  2. Sandoz Center for Immunobiology, Department of Pathology, New England Deaconess Hospital and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts, 02215, USA

    Waune W. Hancock

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  1. Fritz H. Bach
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Bach, F., Ferran, C., Hechenleitner, P. et al. Accommodation of vascularized xenografts: Expression of “protective genes” by donor endothelial cells in a host Th2 cytokine environment. Nat Med 3, 196–204 (1997). https://doi.org/10.1038/nm0297-196

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