Skip to main content

Advertisement

SpringerLink
Log in

Transplantation of Xenogeneic Islets: Are We There Yet?

  • Transplantation (A Pileggi, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Beta cell replacement therapy has been proposed as a novel therapy for the treatment of type 1 diabetes. The proof of concept has been demonstrated with successful islet allotransplantation. Islet xenotransplantation has been proposed as an alternative, more reliable, and infinite source of beta cells. The advantages of islet xenotransplantation are the ability to transplant a well differentiated cell that is responsive to glucose and the potential for genetic modification which focuses the treatment on the donor rather than the recipient. The major hurdle remains overcoming the severe cellular rejection that affects xenografts. This review will focus on the major advances that have occurred with genetic modification and the successful therapeutic strategies that have been demonstrated in nonhuman primates. Novel approaches to overcome cell-mediated rejection including biological agents that target selectively costimulation molecules, the development of local immunosuppression through genetic manipulation, and encapsulation will be discussed. Overall, there has been considerable progress in all these areas, which eventually should lead to clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363:311–20.

    Article  PubMed  CAS  Google Scholar 

  2. Thompson DM, Meloche M, Ao Z, Paty B, Keown P, Shapiro RJ, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. 2011;91:373–8.

    Article  PubMed  Google Scholar 

  3. Tiwari JL, Schneider B, Barton F, Anderson SA. Islet cell transplantation in type 1 diabetes: an analysis of efficacy outcomes and considerations for trial designs. Am J Transplant. 2012;12:1898–907.

    Article  PubMed  CAS  Google Scholar 

  4. Graham KL, Krishnamurthy B, Fynch S, Ayala-Perez R, Slattery RM, Santamaria P, et al. Intra-islet proliferation of cytotoxic T lymphocytes contributes to insulitis progression. Eur J Immunol. 2012;42:1717–22.

    Article  PubMed  CAS  Google Scholar 

  5. Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes. 2002;51:1779–84.

    Article  PubMed  CAS  Google Scholar 

  6. Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Kallen R, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002;360:2039–45.

    Article  PubMed  CAS  Google Scholar 

  7. Bennet W, Sundberg B, Groth CG, et al. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes. 1999;48:1907–14.

    Article  PubMed  CAS  Google Scholar 

  8. • Ji M, Yi S, Smith-Hurst H, Phillips P, Wu J, Hawthorne W, et al. The importance of tissue factor expression by porcine NICC in triggering IBMIR in the xenograft setting. Transplantation. 2011;91:841–6. This paper shows that reduction in tissue factor expression will lead to a reduction in the severity of IBMIR.

    Article  PubMed  Google Scholar 

  9. Cowan PJ, d’Apice AJ. The coagulation barrier in xenotransplantation: incompatibilities and strategies to overcome them. Curr Opin Organ Transplant. 2008;13:178–83.

    Article  PubMed  Google Scholar 

  10. Hamad OA, Back J, Nilsson PH, Nilsson B, Ekdahl KN. Platelets, complement, and contact activation: partners in inflammation and thrombosis. Adv Exp Med Biol. 2012;946:185–205.

    Article  PubMed  CAS  Google Scholar 

  11. Owens III AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res. 2011;108:1284–97.

    Article  PubMed  CAS  Google Scholar 

  12. Rayat GR, Rajotte RV, Hering BJ, Binette TM, Korbutt GS. In vitro and in vivo expression of Galalpha-(1,3)Gal on porcine islet cells is age dependent. J Endocrinol. 2003;177:127–35.

    Article  PubMed  CAS  Google Scholar 

  13. van der Windt DJ, Bottino R, Casu A, Campanile N, Cooper DK. Rapid loss of intraportally transplanted islets: an overview of pathophysiology and preventive strategies. Xenotransplantation. 2007;14:288–97.

    Article  PubMed  Google Scholar 

  14. Contreras J, Eckstein C, Smyth CA, Bilbao G, Vilatoba M, Ringland SE, et al. Activated protein C preserves functional islet mass after intraportal transplantation: a novel link between endothelial cell activation, thrombosis, inflammation, and islet cell death. Diabetes. 2004;53:2804–14.

    Article  PubMed  CAS  Google Scholar 

  15. Akima S, Hawthorne WJ, Koutts J, et al, editor. Differences in the efficacy of recombinant human activated protein C against allogeneic and xenogeneic IBMIR. 24th annual scientific meeting of the TSANZ. Austalian Academy of Science, Canberra; 2006.

  16. Lundgren T, Bennet W, Tibell A, Soderlund J, Sundberg B, Song Z, et al. Soluble complement receptor 1 (TP10) preserves adult porcine islet morphology after intraportal transplantation into cynomolgus monkeys. Transplant Proc. 2001;33:725.

    Article  PubMed  CAS  Google Scholar 

  17. Ryan EA, Lakey JR, Rajotte RV, et al. Clincal outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001;50:710–9.

    Article  PubMed  CAS  Google Scholar 

  18. Villiger P, Ryan EA, Owen R, O’Kelly K, Oberholzer J, Al Saif F, et al. Prevention of bleeding after islet transplantation: lessons learned from a multivariate analysis of 132 cases at a single institution. Am J Transplant. 2005;5:2992–8.

    Article  PubMed  CAS  Google Scholar 

  19. Moberg L, Olsson A, Berne C, Felldin M, Foss A, Kallen R, et al. Nicotinamide inhibits tissue factor expression in isolated human pancreatic islets: implications for clinical islet transplantation. Transplantation. 2003;76:1285–8.

    Article  PubMed  CAS  Google Scholar 

  20. Cabric S, Sanchez J, Johansson U, Larsson R, Nilsson B, Korsgren O, et al. Anchoring of vascular endothelial growth factor to surface-immobilized heparin on pancreatic islets: implications for stimulating islet angiogenesis. Tissue Eng. 2010;16:961–70.

    Article  CAS  Google Scholar 

  21. Gill RG, Wolf L, Daniel D, Coulombe M. CD4+ T-cells are both necessary and sufficient for islet xenograft rejection. Transplant Proc. 1994;26:1203.

    PubMed  CAS  Google Scholar 

  22. Loudovaris T, Mandel TE, Charlton B. CD4+ T-cell mediated destruction of xenografts within cell-impermeable membranes in the absence of CD8+ T-cells and B cells. Transplantation. 1996;61:1678–84.

    Article  PubMed  CAS  Google Scholar 

  23. Xu BY, Yang H, Serreze DV, MacIntosh R, Yu W, Wright Jr JR. Rapid destruction of encapsulated islet xenografts by NOD mice is CD4-dependent and facilitated by B-cells: innate immunity and autoimmunity do not play significant roles. Transplantation. 2005;80:402–9.

    Article  PubMed  CAS  Google Scholar 

  24. Simeonovic CJ, Ceredig R, Wilson JD. Effect of GK1.5 monoclonal antibody dosage on survival of pig proislet xenografts in CD4+ T-cell-depleted mice. Transplantation. 1990;49:849–56.

    Article  PubMed  CAS  Google Scholar 

  25. Koulmanda M, McKenzie I, Sandrin M, Mandel T. Fetal pig xenografts in NOD/Lt mice: lack of expression of Gal(alpha 1–3)Gal on endocrine cells and the effect of peritransplant anti-CD4 monoclonal antibody and graft immunomodification on graft survival. Transplant Proc. 1995;27:3570.

    PubMed  CAS  Google Scholar 

  26. Yi S, Feng X, Hawthorne WJ, Patel AT, Walters SN, O’Connell PJ. CD4+ T-cells initiate pancreatic islet xenograft rejection via an interferon-gamma-dependent recruitment of macrophages and natural killer cells. Transplantation. 2002;73:437–46.

    Article  PubMed  Google Scholar 

  27. • Yi S, Ji M, Wu J, Ma X, Phillips P, Hawthorne WJ, et al. Adoptive transfer with in vitro expanded human regulatory T-cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes. 2012;61:1180–91. This manuscript shows that the human T-cell response to islet xenografts can be modified and suppressed by expanded naïve Treg cells that secrete IL-10.

    Google Scholar 

  28. Friedman T, Smith RN, Colvin RB, Iacomini J. A critical role for human CD4+ T-cells in rejection of porcine islet cell xenografts. Diabetes. 1999;48:2340–8.

    Article  PubMed  CAS  Google Scholar 

  29. Tonomura N, Shimizu A, Wang S, Yamada K, Tchipashvili V, Weir GC, et al. Pig islet xenograft rejection in a mouse model with an established human immune system. Xenotransplantation. 2008;15:129–35.

    Article  PubMed  Google Scholar 

  30. Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med. 2006;12:301–3.

    Article  PubMed  CAS  Google Scholar 

  31. Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006;12:304–6.

    Article  PubMed  CAS  Google Scholar 

  32. Yamada K, Sachs DH, DerSimonian H. Human anti-porcine xenogeneic T-cell response. Evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition. J Immunol. 1995;155:5249–56.

    PubMed  CAS  Google Scholar 

  33. Murray AG, Khodadoust MM, Pober JS, Bothwell AL. Porcine aortic endothelial cells activate human T-cells: direct presentation of MHC antigens and costimulation by ligands for human CD2 and CD28. Immunity. 1994;1:57–63.

    Article  PubMed  CAS  Google Scholar 

  34. Koulmanda M, Laufer TM, Auchincloss Jr H, Smith RN. Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response. Xenotransplantation. 2004;11:525–30.

    Article  PubMed  Google Scholar 

  35. Olack BJ, Jaramillo A, Benshoff ND, Kaleem Z, Swanson CJ, Lowell JA, et al. Rejection of porcine islet xenografts mediated by CD4+ T-cells activated through the indirect antigen recognition pathway. Xenotransplantation. 2002;9:393–401.

    Article  PubMed  Google Scholar 

  36. Auchincloss Jr H, Sachs DH. Xenogeneic transplantation. Annu Rev Immunol. 1998;16:433–70.

    Article  PubMed  CAS  Google Scholar 

  37. Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future. Nat Rev. 2007;7:519–31.

    CAS  Google Scholar 

  38. Schmidt P, Krook H, Maeda A, Korsgren O, Benda B. A new murine model of islet xenograft rejection: graft destruction is dependent on a major histocompatibility-specific interaction between T-cells and macrophages. Diabetes. 2003;52:1111–8.

    Article  PubMed  CAS  Google Scholar 

  39. Wu GS, Korsgren O, Zhang JG, Song ZS, Van Rooijen N, Tibell A. Role of macrophages and natural killer cells in the rejection of pig islet xenografts in mice. Transplant Proc. 2000;32:1069.

    Article  PubMed  CAS  Google Scholar 

  40. Andres A, Toso C, Morel P, Bosco D, Bucher P, Oberholzer J, et al. Macrophage depletion prolongs discordant but not concordant islet xenograft survival. Transplantation. 2005;79:543–9.

    Article  PubMed  Google Scholar 

  41. Yi S, Hawthorne WJ, Lehnert AM, Ha H, Wong JK, van Rooijen N, et al. T-cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts. J Immunol. 2003;170:2750–8.

    PubMed  CAS  Google Scholar 

  42. Chang TM. Therapeutic applications of polymeric artificial cells. Nat Rev Drug Discov. 2005;4:221–35.

    Article  PubMed  CAS  Google Scholar 

  43. • Carlson DF, Tan W, Lillico SG, Stverakova D, Proudfoot C, Christian M, et al. Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci U S A. 2012;109:17382–7. This paper highlights some of the efficiencies in livestock cloning and gene modification that may benefit islet xenotransplantation. It shows that TALEN represents a highly facile platform for the modification of livestock genomes for both biomedical and agricultural applications.

    Article  PubMed  CAS  Google Scholar 

  44. • Fisicaro N, Londrigan SL, Brady JL, Salvaris E, Nottle MB, O’Connell PJ, et al. Versatile co-expression of graft-protective proteins using 2A-linked cassettes. Xenotransplantation. 2011;18:121–30. Describes how the 2A ribosome skip isgnal can be used to express several transgenes with different processing and localizing mechanisms in a single transgenic construct.

    Article  PubMed  Google Scholar 

  45. Nilsson B, Ekdahl KN, Korsgren O. Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant. 2011;16:620–6.

    Article  PubMed  CAS  Google Scholar 

  46. Cowan PJ, d’Apice AJ. Complement activation and coagulation in xenotransplantation. Immunol Cell Biol. 2009;87:203–8.

    Article  PubMed  CAS  Google Scholar 

  47. •• Thompson P, Badell IR, Lowe M, Cano J, Song M, Leopardi F, et al. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011;11:2593–602. This paper shows the benefits of using genetically modified pigs to enhance survival. It shows that removal of the αGal antigen enhances islet xenograft survival in nonhuman primates.

    Article  PubMed  CAS  Google Scholar 

  48. van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, et al. Long-term controlled normoglycemia in diabetic nonhuman primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant. 2009;9:2716–26.

    Article  PubMed  Google Scholar 

  49. Wheeler DG, Joseph ME, Mahamud SD, Aurand WL, Mohler PJ, Pompili VJ, et al. Transgenic swine: expression of human CD39 protects against myocardial injury. J Mol Cell Cardiol. 2012;52:958–61.

    Article  PubMed  CAS  Google Scholar 

  50. Yazaki S, Iwamoto M, Onishi A, Miwa Y, Hashimoto M, Oishi T, et al. Production of cloned pigs expressing human thrombomodulin in endothelial cells. Xenotransplantation. 2012;19:82–91.

    Article  PubMed  Google Scholar 

  51. Dwyer KM, Mysore TB, Crikis S, Robson SC, Nandurkar H, Cowan PJ, et al. The transgenic expression of human CD39 on murine islets inhibits clotting of human blood. Transplantation. 2006;82:428–32 [Epub 2006/08/15].

    Article  PubMed  CAS  Google Scholar 

  52. Schneider MK, Seebach JD. Current cellular innate immune hurdles in pig-to-primate xenotransplantation. Curr Opin Organ Transplant. 2008;13:171–7.

    Article  PubMed  Google Scholar 

  53. Wang H, Yang YG. Innate cellular immunity and xenotransplantation. Curr Opin Organ Transplant. 2012;17:162–7.

    Article  PubMed  CAS  Google Scholar 

  54. Weiss EH, Lilienfeld BG, Muller S, Muller E, Herbach N, Kessler B, et al. HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation. 2009;87:35–43.

    Article  PubMed  CAS  Google Scholar 

  55. Ide K, Wang H, Tahara H, Liu J, Wang X, Asahara T, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci U S A. 2007;104:5062–6.

    Article  PubMed  CAS  Google Scholar 

  56. •• Klymiuk N, van Buerck L, Bahr A, Offers M, Kessler B, Wuensch A, et al. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes. 2012;61:1527–32. This important paper describes the generation of transgenic pigs expressing LEA29Y, a high-affinity variant of the T-cell costimulation inhibitor CTLA-4Ig, under the control of the porcine insulin gene promoter. NICC from these pigs were able to ovoid rejection by human T-cells in a humanized mouse model of islet xenotransplantation and shows the utility of local immunosuppression for protecting the graft.

    Article  PubMed  CAS  Google Scholar 

  57. Brady JL, Mannering SI, Kireta S, Coates PT, Proietto AI, Cowan PJ, et al. Monoclonal antibodies generated by DNA immunization recognize CD2 from a broad range of primates. Immunol Cell Biol. 2009;87:413–8.

    Article  PubMed  CAS  Google Scholar 

  58. Lowe M, Badell IR, Thompson P, Martin B, Leopardi F, Strobert E, et al. A novel monoclonal antibody to CD40 prolongs islet allograft survival. Am J Transplant. 2012;12:2079–87.

    Article  PubMed  CAS  Google Scholar 

  59. Lowe MC, Badell IR, Turner AP, Thompson PW, Leopardi FV, Strobert EA, et al. Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. Am J Transplant. 2013;13:312–9.

    Article  PubMed  CAS  Google Scholar 

  60. Carrington EM, Vikstrom IB, Light A, Sutherland RM, Londrigan SL, Mason KD, et al. BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc Natl Acad Sci U S A. 2010;107:10967–71.

    Article  PubMed  CAS  Google Scholar 

  61. Khattar M, Deng R, Kahan BD, Schroder PM, Phan T, Rutzky LP, et al. Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T-cells induces permanent acceptance of pancreatic islet allografts. Transplantation. 2013;95:919–27.

    Google Scholar 

  62. Geissler EK. Fighting malignancy in organ transplant recipients. Transplant Proc. 2009;41(6 Suppl):S9–12.

    Article  PubMed  CAS  Google Scholar 

  63. • Brady JL, Sutherland RM, Hancock M, Kitsoulis S, Lahoud MH, Phillips PM, et al. Anti-CD2 producing pig xenografts effect localized depletion of human T-cells in a huSCID model. Xenotransplantation. 2013;20:100–9. This paper demonstrates the potential benefits of local immunosuppression and its ability to avoid systemic immunosuppression. Local production of a single Ab against T-cells reduced graft infiltration at the xenograft site and may reduce the need for conventional, systemic immunosuppression.

  64. Londrigan SL, Sutherland RM, Brady JL, Carrington EM, Cowan PJ, d’Apice AJ, et al. In situ protection against islet allograft rejection by CTLA4Ig transduction. Transplantation. 2010;90:951–7.

    Article  PubMed  CAS  Google Scholar 

  65. Ramji QA, Bayrack K, Arefanian H, Marcet-Palacios M, Bleackley RC, Rajotte RV, et al. Protection of porcine islet xenografts in mice using sertoli cells and monoclonal antibodies. Transplantation. 2011;92:1309–15.

    Article  PubMed  CAS  Google Scholar 

  66. Reading JL, Sabbah S, Busch S, Tree TI. Mesenchymal stromal cells as a means of controlling pathological T-cell responses in allogeneic islet transplantation. Curr Opin Organ Transplant. 2013;18:59–64.

    Article  PubMed  CAS  Google Scholar 

  67. Sun G, Shan J, Li Y, Zhou Y, Guo Y, Wu W, et al. Adoptive infusion of tolerogenic dendritic cells prolongs the survival of pancreatic islet allografts: a systematic review of 13 mouse and rat studies. PLoS One. 2012;7:e52096.

    Article  PubMed  CAS  Google Scholar 

  68. •• Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90:1054–62. A very important paper showing that Pig islets encapsulated in a subcutaneous alginate macrodevice can control diabetes up to 6 months without immunosuppression in nonhuman primates.

    Article  PubMed  Google Scholar 

  69. •• Thompson P, Cardona K, Russell M, Badell IR, Shaffer V, Korbutt G, et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant. 2011;11:947–57. Most studies that have shown long term islet xenograft survival in primates have relied on administration of anti-CD154 mAb to prevent rejection. This agent cannot be used clinically. This study showed that anti-CD154 mAb could be substituted with an anti-CD40 mAb and enable functioning islet xenograft survival. Hence, it may form the basis of an immunosuppressive protocol that could be taken to the clinic.

    Article  PubMed  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Philip J. O’Connell declares that he has no conflict of interest.

Peter J. Cowan has received grant support from National Health & Medical Research Council of Australia; Juvenile Diabetes Research Foundation (Program Grant #447718: Which transgenic pig will be used for islet transplantation in humans?).

Wayne J. Hawthorne declares that he has no conflict of interest.

Shounan Yi declares that he has no conflict of interest.

Andrew M. Lew has received grant support from National Health & Medical Research Council and Juvenile Diabetes Research Foundation for diabetes research. He has also received support in kind such as writing, provision of medicines or equipment, or administrative support from Victorian state government for support for infrastructure costs.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia

    Philip J. O’Connell, Wayne J. Hawthorne & Shounan Yi

  2. Immunology Research Centre, St Vincent’s Hospital, Melbourne, Victoria, Australia

    Peter J. Cowan

  3. Department of Medicine, University of Melbourne, Melbourne, Australia

    Peter J. Cowan

  4. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia

    Andrew M. Lew

Authors
  1. Philip J. O’Connell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Cowan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wayne J. Hawthorne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shounan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew M. Lew
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip J. O’Connell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O’Connell, P.J., Cowan, P.J., Hawthorne, W.J. et al. Transplantation of Xenogeneic Islets: Are We There Yet?. Curr Diab Rep 13, 687–694 (2013). https://doi.org/10.1007/s11892-013-0413-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-013-0413-9

Keywords

Search

Navigation