Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Prolongation of islet allograft survival following ex vivo transduction with adenovirus encoding a soluble type 1 TNF receptor–Ig fusion decoy

Abstract

Islet transplantation is a viable long-term therapeutic alternative to daily insulin replacement for type I diabetes. The allogeneic nature of the transplants poses immunological challenges for routine clinical utility. Gene transfer of immunoregulatory molecules and those that improve insulin release kinetics provides rational approaches to facilitate allogeneic islet transplantation as a potential therapy. We have examined the efficacy of a soluble type 1 tumor necrosis factor receptor (TNFR) immunoglobulin-Fc fusion transgene (TNFR–Ig) to protect human islets from cytokine-induced apoptosis in culture, as well as in facilitating allogeneic islet transplants in diabetic mice. Cultured human islets were transduced with an adenoviral vector encoding human TNFR–Ig (Ad-TNFR–Ig). TNFR–Ig protein was secreted by cultured islets, as well as by transduced mouse islet transplants recovered from mouse recipients. Glucose-induced insulin release kinetics were comparable among untransduced, Ad-TNFR–Ig-infected human islets and vector-transduced islets exposed to cytokines. In parallel, Ad-TNFR–Ig-infected islets were protected from cytokine-induced apoptosis activation. Finally, diabetic mice transplanted with allogeneic islets expressing TNFR–Ig returned to and maintained normoglycemia significantly longer than untransduced islet recipients. These data support the potential utility of TNFR–Ig gene transfer to islets as a means of facilitating allogeneic islet transplantation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ryan EA et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001; 50: 710–719.

    Article  CAS  Google Scholar 

  2. Ryan EA, Lakey JR, Shapiro AM . Clinical results after islet transplantation. J Investig Med 2001; 49: 559–562.

    Article  CAS  Google Scholar 

  3. Shapiro AM et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230–238.

    Article  CAS  Google Scholar 

  4. Bottino R et al. Preservation of human islet cell functional mass by anti-oxidative action of a novel SOD mimic compound. Diabetes 2002; 51: 2561–2567.

    Article  CAS  Google Scholar 

  5. Piganelli JD et al. A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. Diabetes 2002; 51: 347–355.

    Article  CAS  Google Scholar 

  6. Nickerson P et al. Analysis of cytokine transcripts in pancreatic islet cell allografts during rejection and tolerance induction. Transplant Proc 1993; 25: 984–985.

    CAS  PubMed  Google Scholar 

  7. Rabinovitch A, Suarez-Pinzon WL . Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 1998; 55: 1139–1149.

    Article  CAS  Google Scholar 

  8. Suarez-Pinzon WL, Strynadka K, Rabinovitch A . Destruction of rat pancreatic islet beta-cells by cytokines involves the production of cytotoxic aldehydes. Endocrinology 1996; 137: 5290–5296.

    Article  CAS  Google Scholar 

  9. Bottino R et al. Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 1998; 47: 316–323.

    Article  CAS  Google Scholar 

  10. Langrehr JM, White DA, Hoffman RA, Simmons RL . Macrophages produce nitric oxide at allograft sites. Ann Surg 1993; 218: 159–166.

    Article  CAS  Google Scholar 

  11. Lentsch AB et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology 1998; 27: 507–512.

    Article  CAS  Google Scholar 

  12. Lentsch AB et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and KC. Hepatology 1998; 27: 1172–1177.

    Article  CAS  Google Scholar 

  13. Sekine Y et al. Role of passenger leukocytes in allograft rejection: effect of depletion of donor alveolar macrophages on the local production of TNF-alpha, T helper 1/T helper 2 cytokines, IgG subclasses, and pathology in a rat model of lung transplantation. J Immunol 1997; 159: 4084–4093.

    CAS  PubMed  Google Scholar 

  14. Dahlen E, Dawe K, Ohlsson L, Hedlund G . Dendritic cells and macrophages are the first and major producers of TNF-alpha in pancreatic islets in the nonobese diabetic mouse. J Immunol 1998; 160: 3585–3593.

    CAS  Google Scholar 

  15. Jobin C et al. TNF receptor-associated factor-2 is involved in both IL-1 beta and TNF-alpha signaling cascades leading to NF-kappa B activation and IL-8 expression in human intestinal epithelial cells. J Immunol 1999; 162: 4447–4454.

    CAS  PubMed  Google Scholar 

  16. Kagi D et al. TNF receptor 1-dependent beta cell toxicity as an effector pathway in autoimmune diabetes. J Immunol 1999; 162: 4598–4605.

    CAS  Google Scholar 

  17. Arnush M et al. Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J Immunol 1998; 160: 2684–2691.

    CAS  Google Scholar 

  18. Arnush M et al. IL-1 produced and released endogenously within human islets inhibits beta cell function. J Clin Invest 1998; 102: 516–526.

    Article  CAS  Google Scholar 

  19. Azzawi M, Hasleton P . Tumour necrosis factor alpha and the cardiovascular system: its role in cardiac allograft rejection and heart disease. Cardiovasc Res 1999; 43: 850–859.

    Article  CAS  Google Scholar 

  20. Soldevila G et al. Cytotoxic effect of IFN-gamma plus TNF-alpha on human islet cells. J Autoimmun 1991; 4: 291–306.

    Article  CAS  Google Scholar 

  21. Suk K et al. IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J Immunol 2001; 166: 4481–4489.

    Article  CAS  Google Scholar 

  22. Kagi D et al. TNF receptor 1-dependent beta cell toxicity as an effector pathway in autoimmune diabetes. J Immunol 1999; 162: 4598–4605.

    CAS  Google Scholar 

  23. Held W et al. Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 1990; 87: 2239–2243.

    Article  CAS  Google Scholar 

  24. Yang XD et al. Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med 1994; 180: 995–1004.

    Article  CAS  Google Scholar 

  25. Hunger RE et al. Prevention of autoimmune diabetes mellitus in NOD mice by transgenic expression of soluble tumor necrosis factor receptor p55. Eur J Immunol 1997; 27: 255–261.

    Article  CAS  Google Scholar 

  26. Farney AC et al. Inhibition of pancreatic islet beta cell function by tumor necrosis factor is blocked by a soluble tumor necrosis factor receptor. Transplant Proc 1993; 25: 865–866.

    CAS  PubMed  Google Scholar 

  27. Xenos ES et al. Effect of tumor necrosis factor alpha and of the soluble tumor necrosis factor receptor on insulin secretion of isolated islets of Langerhans. Transplant Proc 1992; 24: 2863–2864.

    CAS  PubMed  Google Scholar 

  28. Robbins PD, Evans CH, Chernajovsky Y . Gene therapy for arthritis. Gene Therapy 2003; 10: 902–911.

    Article  CAS  Google Scholar 

  29. Chernajovsky Y . Systemic gene therapy for arthritis. Drugs Today (Barc) 1999; 35: 361–377.

    Article  CAS  Google Scholar 

  30. Csete ME et al. Adenoviral-mediated gene transfer to pancreatic islets does not alter islet function. Transplant Proc 1994; 26: 756–757.

    CAS  Google Scholar 

  31. Csete ME et al. Efficient gene transfer to pancreatic islets mediated by adenoviral vectors. Transplantation 1995; 59: 263–268.

    Article  CAS  Google Scholar 

  32. Weber M et al. Adenoviral transfection of isolated pancreatic islets: a study of programmed cell death (apoptosis) and islet function. J Surg Res 1997; 69: 23–32.

    Article  CAS  Google Scholar 

  33. Giannoukakis N et al. Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro. Diabetes 1999; 48: 1730–1736.

    Article  CAS  Google Scholar 

  34. Giannoukakis N, Rudert WA, Trucco M, Robbins PD . Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. J Biol Chem 2000; 275: 36509–36513.

    Article  CAS  Google Scholar 

  35. Giannoukakis N et al. Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I. Gene Therapy 2000; 7: 2015–2022.

    Article  CAS  Google Scholar 

  36. Ma Z et al. Interleukin-1 enhances pancreatic islet arachidonic acid 12-lipoxygenase product generation by increasing substrate availability through a nitric oxide-dependent mechanism. J Biol Chem 1996; 271: 1029–1042.

    Article  CAS  Google Scholar 

  37. Rabinovitch A, Pukel C, Baquerizo H . Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures. Endocrinology 1988; 122: 2393–2398.

    Article  CAS  Google Scholar 

  38. Rabinovitch A et al. Human pancreatic islet beta-cell destruction by cytokines involves oxygen free radicals and aldehyde production. J Clin Endocrinol Metab 1996; 81: 3197–3202.

    CAS  Google Scholar 

  39. Rabinovitch A et al. Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects beta-cells from cytokine-induced destruction. Diabetes 1999; 48: 1223–1229.

    Article  CAS  Google Scholar 

  40. Bertera S et al. Gene transfer of manganese superoxide dismutase extends islet graft function in a mouse model of autoimmune diabetes. Diabetes 2003; 52: 387–393.

    Article  CAS  Google Scholar 

  41. Alexander AM et al. Indoleamine 2,3-dioxygenase expression in transplanted NOD islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes 2002; 51: 356–365.

    Article  CAS  Google Scholar 

  42. Bertera S et al. Immunology of type 1 diabetes. Intervention and prevention strategies. Endocrinol Metab Clin North Am 1999; 28: 841–864.

    Article  CAS  Google Scholar 

  43. de Vries RR, Roep BO . Clinical and preclinical immunology of type 1 diabetes. Neth J Med 1998; 53: 127–129.

    Article  CAS  Google Scholar 

  44. Rabinovitch A . An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1998; 14: 129–151.

    Article  CAS  Google Scholar 

  45. Giannoukakis N, Thomson A, Robbins P . Gene therapy in transplantation. Gene Therapy 1999; 6: 1499–1511.

    Article  CAS  Google Scholar 

  46. Giannoukakis N, Rudert WA, Robbins PD, Trucco M . Targeting autoimmune diabetes with gene therapy. Diabetes 1999; 48: 2107–2121.

    Article  CAS  Google Scholar 

  47. Steinman RM et al. The sensitization phase of T-cell-mediated immunity. Ann N Y Acad Sci 1988; 546: 80–90.

    Article  CAS  Google Scholar 

  48. Iwasaki A . The importance of CD11b+ dendritic cells in CD4+ T cell activation in vivo: with help from interleukin 1. J Exp Med 2003; 198: 185–190.

    Article  CAS  Google Scholar 

  49. Petranyi GG . The complexity of immune and alloimmune response. Transpl Immunol 2002; 10: 91–100.

    Article  CAS  Google Scholar 

  50. Steinman RM . Cytokines amplify the function of accessory cells. Immunol Lett 1988; 17: 197–202.

    Article  CAS  Google Scholar 

  51. Kasuga A et al. The role of cytotoxic macrophages in non-obese diabetic mice: cytotoxicity against murine mastocytoma and beta-cell lines. Diabetologia 1993; 36: 1252–1257.

    Article  CAS  Google Scholar 

  52. Kaufman DB et al. Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts. J Exp Med 1990; 172: 291–302.

    Article  CAS  Google Scholar 

  53. Christianson SW, Shultz LD, Leiter EH . Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD. NON-Thy-1a donors. Diabetes 1993; 42: 44–55.

    Article  CAS  Google Scholar 

  54. Hanenberg H, Kolb-Bachofen V, Kantwerk-Funke G, Kolb H . Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia 1989; 32: 126–134.

    Article  CAS  Google Scholar 

  55. Li XB, Scott FW, Park YH, Yoon JW . Low incidence of autoimmune type I diabetes in BB rats fed a hydrolysed casein-based diet associated with early inhibition of non-macrophage-dependent hyperexpression of MHC class I molecules on beta cells. Diabetologia 1995; 38: 1138–1147.

    Article  CAS  Google Scholar 

  56. Corbett JA et al. Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. J Clin Invest 1992; 90: 2384–2391.

    Article  CAS  Google Scholar 

  57. Corbett JA et al. Nitric oxide and cyclic GMP formation induced by interleukin 1 beta in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction. Biochem J 1992; 287: 229–235.

    Article  CAS  Google Scholar 

  58. Heitmeier MR, Scarim AL, Corbett JA . Interferon-gamma increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1. J Biol Chem 1997; 272: 13697–13704.

    Article  CAS  Google Scholar 

  59. Corbett JA, McDaniel ML . Reversibility of interleukin-1 beta-induced islet destruction and dysfunction by the inhibition of nitric oxide synthase. Biochem J 1994; 299: 719–724.

    Article  CAS  Google Scholar 

  60. Carlquist JF et al. Cytokines and rejection of mouse cardiac allografts. Transplantation 1996; 62: 1160–1166.

    Article  CAS  Google Scholar 

  61. Chandler C, Passaro Jr E . Transplant rejection. Mechanisms and treatment. Arch Surg 1993; 128: 279–283.

    Article  CAS  Google Scholar 

  62. Cosenza CA et al. Intragraft cytokine gene expression in human liver allografts. Liver Transpl Surg 1995; 1: 16–22.

    Article  CAS  Google Scholar 

  63. Delaney CA et al. Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology 1997; 138: 2610–2614.

    Article  CAS  Google Scholar 

  64. Rehman KK et al. Protection of islets by in situ peptide mediated transduction of the Ikappa B kinase (IKK) inhibitor nemo binding domain (NBD) peptide. J Biol Chem 2003; 9: 9.

    Google Scholar 

  65. Li X, Commane M, Jiang Z, Stark GR . IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK). Proc Natl Acad Sci USA 2001; 98: 4461–4465.

    Article  CAS  Google Scholar 

  66. Takatsuna H et al. Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling. J Biol Chem 2003; 278: 12144–12150.

    Article  CAS  Google Scholar 

  67. Suzuki N, Suzuki S, Yeh WC . IRAK-4 as the central TIR signaling mediator in innate immunity. Trends Immunol 2002; 23: 503–506.

    Article  CAS  Google Scholar 

  68. Ruckdeschel K, Mannel O, Schrottner P . Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members. J Immunol 2002; 168: 4601–4611.

    Article  CAS  Google Scholar 

  69. Ferlito M et al. Effect of cross-tolerance between endotoxin and TNF-alpha or IL-1beta on cellular signaling and mediator production. J Leukoc Biol 2001; 70: 821–829.

    CAS  PubMed  Google Scholar 

  70. Worgall S, Wolff G, Falck-Pedersen E, Crystal RG . Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. Hum Gene Ther 1997; 8: 37–44.

    Article  CAS  Google Scholar 

  71. Kajiwara K et al. Immune responses to adenoviral vectors during gene transfer in the brain. Hum Gene Ther 1997; 8: 253–265.

    Article  CAS  Google Scholar 

  72. Kafri T et al. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy. Proc Natl Acad Sci USA 1998; 95: 11377–11382.

    Article  CAS  Google Scholar 

  73. Ritter T, Lehmann M, Volk HD . Improvements in gene therapy: averting the immune response to adenoviral vectors. BioDrugs 2002; 16: 3–10.

    Article  CAS  Google Scholar 

  74. Yeh P, Perricaudet M . Advances in adenoviral vectors: from genetic engineering to their biology. FASEB J 1997; 11: 615–623.

    Article  CAS  Google Scholar 

  75. Ghivizzani SC et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA 1998; 95: 4613–4618.

    Article  CAS  Google Scholar 

  76. Kolls J, Peppel K, Silva M, Beutler B . Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer. Proc Natl Acad Sci USA 1994; 91: 215–219.

    Article  CAS  Google Scholar 

  77. Linetsky E et al. Improved human islet isolation using a new enzyme blend, liberase. Diabetes 1997; 46: 1120–1123.

    Article  CAS  Google Scholar 

  78. Balamurugan AN et al. Flexible management of enzymatic digestion improves human islet isolation outcome from sub-optimal donor pancreata. Am J Transplant 2003; 3: 1135–1142.

    Article  CAS  Google Scholar 

  79. Bertera S et al. Gene transfer of manganese superoxide dismutase extends islet graft function in a mouse model of autoimmune diabetes. Diabetes 2003; 52: 387–393.

    Article  CAS  Google Scholar 

  80. Alexander AM et al. Indoleamine 2,3-dioxygenase expression in transplanted NOD islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes 2002; 51: 356–365.

    Article  CAS  Google Scholar 

  81. Prowse SJ et al. The reversal of diabetes by pancreatic islet transplantation. Diabetes 1982; 31 (Suppl 4): 30–38.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by an NIH grant to NG (DK60183), as well as a program project grant from the Juvenile Diabetes Foundation International (MT and PDR).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Machen, J., Bertera, S., Chang, Y. et al. Prolongation of islet allograft survival following ex vivo transduction with adenovirus encoding a soluble type 1 TNF receptor–Ig fusion decoy. Gene Ther 11, 1506–1514 (2004). https://doi.org/10.1038/sj.gt.3302320

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302320

Keywords

This article is cited by

Search

Quick links