Current Diabetes Reports

, Volume 2, Issue 4, pp 377–382 | Cite as

Alternatives to immunosuppressive drugs in human islet transplantation

  • Alison Anne Cotterell
  • Norma Sue Kenyon
Article

Abstract

Although intensive insulin therapy has resulted in improved metabolic control and decreases in the incidence of complications, the occurrence of severe hypoglycemia remains an issue, as does the continued potential for complications. Islet transplantation, a promising treatment for type 1 diabetes, has been shown to improve blood sugar levels and decrease or even abrogate the incidence of hypoglycemia. The lack of tissue availability and the toxic effects of immunosuppressants, however, limit the application of islet transplantation as a cure for diabetes. This article discusses possible alternatives to immunosuppressive drugs in human islet transplantations.

Keywords

Islet Transplantation Tolerance Induction Allograft Survival Bone Marrow Trans Clinical Islet Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Keen H: The Diabetes Control and Complications Trial (DCCT). Health Trends 1994, 26:41–43.PubMedGoogle Scholar
  2. 2.
    Shapiro AM, Lakey JR, Ryan EA, 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.PubMedCrossRefGoogle Scholar
  3. 3.
    De Vos P, Hamel AF, Tatarkiewicz K: Considerations for successful transplantation of encapsulated pancreatic islets. Diabetologia 2002, 45:159–173. Encapsulation offers a solution to the shortage of donors in clinical islet transplantation because it allows animal islets or insulin-producing cells engineered from stem cells to be used. During the past two decades three major approaches to encapsulation have been studied: 1) intravascular macrocapsules, 2) extravascular macrocapsules, and 3) extravascular microcapsules. The advantages and pitfalls of these three approaches are discussed and compared in light of their applicability to clinical islet transplantation.PubMedCrossRefGoogle Scholar
  4. 4.
    Klomp GF, Ronel SH, Hashiguchi H, et al.: Hydrogels for encapsulation of pancreatic islet cells. Trans Am Soc Artif Intern Organs 1979, 25:74–76.PubMedGoogle Scholar
  5. 5.
    Kessler L, Pinget M, Aprahamian M, et al.: In vitro and in vivo studies of the properties of an artificial membrane for pancreatic islet encapsulation. Horm Metab Res 1991, 23:312–317.PubMedCrossRefGoogle Scholar
  6. 6.
    Lanza RP, Kuhtreiber WM, Ecker DM, et al.: Successful bovine islet xenografts in rodents and dogs using injectable microreactors. Transplant Proc 1995, 27:3211.PubMedGoogle Scholar
  7. 7.
    Knazek RA, Gullino PM, Kohler PO, Dedrick RL: Cell culture on artificial capillaries: an approach to tissue growth in vitro. Science 1972, 178:65–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Chick WL, Like AA, Lauris V: Beta cell culture on synthetic capillaries: an artificial endocrine pancreas. Science 1975, 187:847–849.PubMedCrossRefGoogle Scholar
  9. 9.
    Sun AM, Parisius W, Healy GM, et al.: The use, in diabetic rats and monkeys, of artificial capillary units containing cultured islets of Langerhans (artificial endocrine pancreas). Diabetes 1977, 26:1136–1139.PubMedCrossRefGoogle Scholar
  10. 10.
    Archer J, Kaye R, Mutter G: Control of streptozotocin diabetes in Chinese hamsters by cultured mouse islet cells without immunosuppression: a preliminary report. J Surg Res 1980, 28:77–85.PubMedCrossRefGoogle Scholar
  11. 11.
    Loudovaris T, Jacobs S, Young S, et al.: Correction of diabetic nod mice with insulinomas implanted within Baxter immunoisolation devices. J Mol Med 1999, 77:219–222.PubMedCrossRefGoogle Scholar
  12. 12.
    Lanza RP, Beyer AM, Chick WL: Xenogenic humoral responses to islets transplanted in biohybrid diffusion chambers. Transplantation 1994, 57:1371–1375.PubMedCrossRefGoogle Scholar
  13. 13.
    Jain K, Asina S, Yang H, et al.: Glucose control and long-term survival in biobreeding/Worcester rats after intraperitoneal implantation of hydrophilic macrobeads containing porcine islets without immunosuppression. Transplantation 1999, 68:1693–1700.PubMedCrossRefGoogle Scholar
  14. 14.
    Lacy PE, Hegre OD, Gerasimidi-Vazeou A, et al.: Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets. Science 1991, 254:1782–1784.PubMedCrossRefGoogle Scholar
  15. 15.
    Juang JH, Bonner-Weir S, Ogawa Y, et al.: Outcome of subcutaneous islet transplantation improved by polymer device. Transplantation 1996, 61:1557–1561.PubMedCrossRefGoogle Scholar
  16. 16.
    Juang JH, Bonner-Weir S, Wu YJ, Weir GC: Beneficial influence of glycemic control upon the growth and function of transplanted islets. Diabetes 1994, 43:1334–1339.PubMedCrossRefGoogle Scholar
  17. 17.
    Scharp DW, Swanson CJ, Olack BJ, et al.: Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects. Diabetes 1994, 43:1167–1170.PubMedCrossRefGoogle Scholar
  18. 18.
    Suzuki K, Bonner-Weir S, Trivedi N, et al.: Function and survival of macroencapsulated syngeneic islets transplanted into streptozotocin-diabetic mice. Transplantation 1998, 66:21–28.PubMedCrossRefGoogle Scholar
  19. 19.
    Suzuki K, Bonner-Weir S, Hollister-Lock J, et al.: Number and volume of islet transplanted in immunobarrier devices. Cell Transplant 1998, 7:47–52.PubMedCrossRefGoogle Scholar
  20. 20.
    Tatarkiewicz K, Hollister-Lock J, Quickel RR, et al.: Reversal of hyperglycemia in mice after subcutaneous transplantation of macroencapsulated islets. Transplantation 1999, 67:665–671.PubMedCrossRefGoogle Scholar
  21. 21.
    Siebers U, Zekorn T, Bretzel RG, et al.: Histocompatibility of semi-permeable membranes for implantable diffusion devices (bioartificial pancreas). Transplant Proc 1990, 22:834–835.PubMedGoogle Scholar
  22. 22.
    Soon-Shiong P, Heintz RE, Merideth N, et al.: Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 1994, 343:950–951.PubMedCrossRefGoogle Scholar
  23. 23.
    De Vos P, De Haan BJ, Wolters GH, et al.: Improved biocompatibility but limited graft survival after purification of alginate for microencapsulation of pancreatic islets. Diabetologia 1997, 40:262–270.PubMedCrossRefGoogle Scholar
  24. 24.
    Billingham RE, Brent L, Medawar PB: Actively acquired tolerance to foreign cells. Nature 1953, 172:606.CrossRefGoogle Scholar
  25. 25.
    Owen RD: Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945, 102:400.CrossRefPubMedGoogle Scholar
  26. 26.
    Hartwig M: Control of clonal deletion in the thymus: implications for tolerance induction. Immunol Cell Biol 1993, 71(pt 4):337–340.PubMedGoogle Scholar
  27. 27.
    Kappler JW, Roehm N, Marrack P: T cell tolerance by clonal elimination in the thymus. Cell 1987, 49:273–280.PubMedCrossRefGoogle Scholar
  28. 28.
    MacDonald HR, Howe RC, Pedrazzini T, et al.: T-cell lineages, repertoire selection and tolerance induction. Immunol Rev 1988, 104:157–182.PubMedCrossRefGoogle Scholar
  29. 29.
    Ruedi E, Sykes M, Ildstad ST, et al.: Antiviral T cell competence and restriction specificity of mixed allogeneic (P1 + P2----P1) irradiation chimeras. Cell Immunol 1989, 121:185–195.PubMedCrossRefGoogle Scholar
  30. 30.
    Alinaji WK, Silvers, Bellgrau D, et al.: Prevention of diabetes in rats by bone marrow transplantation. Ann Surg 1981, 194:328–338.PubMedCrossRefGoogle Scholar
  31. 31.
    Colson YL, Zadach K, Nalesnik M, Ildstad ST: Mixed allogeneic chimerism in the rat. Donor-specific transplantation tolerance without chronic rejection for primarily vascularized cardiac allografts. Transplantation 1995, 60:971–980.PubMedCrossRefGoogle Scholar
  32. 32.
    Ildstad ST, Sachs DH: Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 1984, 307:168–170.PubMedCrossRefGoogle Scholar
  33. 33.
    Zeng Y, Ildstad ST, Wren SM, et al.: Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras. Transplant Proc 1992, 24:985.PubMedGoogle Scholar
  34. 34.
    Panijayanond P, Monaco AP: Enhancement of pancreatic islet allograft survival with ALS and donor bone marrow. Surg Forum 1974, 25:379–381.PubMedGoogle Scholar
  35. 35.
    Zeng YJ, Ricordi C, Tzakis A, et al.: Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras (WF rat----B10 mouse). Transplantation 1992, 53:277–283.PubMedCrossRefGoogle Scholar
  36. 36.
    Li H, Ricordi C, Demetris AJ, et al.: Mixed xenogeneic chimerism (mouse+rat--> mouse) to induce donor-specific tolerance to sequential or simultaneous islet xenografts. Transplantation 1994, 57:592–598.PubMedCrossRefGoogle Scholar
  37. 37.
    Burke GW, Ricordi C, Karatzas T, et al.: Donor bone marrow infusion in simultaneous pancreas/kidney transplantation with OKT3 induction: evidence for augmentation of chimerism. Transplant Proc 1997, 29:1207–1208.PubMedCrossRefGoogle Scholar
  38. 38.
    Burke GW, Ricordi C, Karatzas T, et al.: Donor bone marrow infusion in simultaneous pancreas/kidney transplant recipients: a preliminary study. Transplant Proc 1995, 27:3121–3122.PubMedGoogle Scholar
  39. 39.
    Cheta D: Animal models of type I (insulin-dependent) diabetes mellitus. J Pediatr Endocrinol Metab 1998, 11:11–19. The main models of insulin-dependent diabetes mellitus (IDDM) may be divided into two groups: induced and spontaneous. Studies aimed at preventing IDDM have advanced by leaps and bounds by using the two spontaneous models. The conclusions drawn from animal experiments have allowed some human trials to be carried out with encouraging results.PubMedGoogle Scholar
  40. 40.
    Knechtle SJ, Zhai Y, Fechner J: Gene therapy in transplantation. Transpl Immunol 1996, 4:257–264.PubMedCrossRefGoogle Scholar
  41. 41.
    Qin L, Chavin KD, Ding Y, et al.: Gene transfer for transplantation. Prolongation of allograft survival with transforming growth factor-beta 1. Ann Surg 1994, 220:508–518; discussion 518–519.PubMedCrossRefGoogle Scholar
  42. 42.
    Qin L, Chavin KD, Ding Y, et al.: Multiple vectors effectively achieve gene transfer in a murine cardiac transplantation model. Immunosuppression with TGF-beta 1 or vIL-10. Transplantation 1995, 59:809–816.PubMedCrossRefGoogle Scholar
  43. 43.
    Madsen JC, Superina RA, Wood KJ, Morris PJ: Immunological unresponsiveness induced by recipient cells transfected with donor MHC genes. Nature 1988, 332:161–164.PubMedCrossRefGoogle Scholar
  44. 44.
    Csete ME, Afra R, Mullen Y, et al.: Adenoviral-mediated gene transfer to pancreatic islets does not alter islet function. Transplant Proc 1994, 26:756–757.PubMedGoogle Scholar
  45. 45.
    Csete ME, Benhamou PY, Drazan KE, et al.: Efficient gene transfer to pancreatic islets mediated by adenoviral vectors. Transplantation 1995, 59:263–268.PubMedCrossRefGoogle Scholar
  46. 46.
    Chahine AA, Yu M, McKernan M, et al.: Local CTLA4Ig synergizes with one-dose anti-LFA-1 to achieve long-term acceptance of pancreatic islet allografts. Transplant Proc 1994, 26:3296.PubMedGoogle Scholar
  47. 47.
    Limmer A, Ohl J, Kurts C, et al.: Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 2000, 6:1348–1354.PubMedCrossRefGoogle Scholar
  48. 48.
    Josien R, Heslan M, Brouard S, et al.: Critical requirement for graft passenger leukocytes in allograft tolerance induced by donor blood transfusion. Blood 1998, 92:4539–4544.PubMedGoogle Scholar
  49. 49.
    Stumbles PA, Thomas JA, Pimm CL, et al.: Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med 1998, 188:2019–2031.PubMedCrossRefGoogle Scholar
  50. 50.
    Inaba K, Turley S, Iyoda T, et al.: The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J Exp Med 2000, 191:927–936.PubMedCrossRefGoogle Scholar
  51. 51.
    Schuurhuis DH, Laban S, Toes RE, et al.: Immature dendritic cells acquire CD8(+) cytotoxic T lymphocyte priming capacity upon activation by T helper cell-independent or -dependent stimuli. J Exp Med 2000, 192:145–150.PubMedCrossRefGoogle Scholar
  52. 52.
    Forster I, Lieberam I: Peripheral tolerance of CD4 T cells following local activation in adolescent mice. Eur J Immunol 1996, 26:3194–3202.PubMedCrossRefGoogle Scholar
  53. 53.
    Kurts C, Kosaka H, Carbone FR, et al.: Class I-restricted crosspresentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells. J Exp Med 1997, 186:239–245.PubMedCrossRefGoogle Scholar
  54. 54.
    Morgan DJ, Kreuwel HT, Sherman LA: Antigen concentration and precursor frequency determine the rate of CD8+ T cell tolerance to peripherally expressed antigens. J Immunol 1999, 163:723–727.PubMedGoogle Scholar
  55. 55.
    Adler AJ, Marsh DW, Yochum GS, et al.: CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells. J Exp Med 1998, 187:1555–1564.PubMedCrossRefGoogle Scholar
  56. 56.
    Jonuleit H, Schmitt E, Schuler G, et al.: Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000, 192:1213–1222.PubMedCrossRefGoogle Scholar
  57. 57.
    Dhodapkar MV, Steinman RM, Krasovsky J, et al.: Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001, 193:233–238.PubMedCrossRefGoogle Scholar
  58. 58.
    Groux H, O'Garra A, Bigler M, et al.: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997, 389:737–742.PubMedCrossRefGoogle Scholar
  59. 59.
    Shevach EM: Regulatory T cells in autoimmmunity. Annu Rev Immunol 2000, 18:423–449.PubMedCrossRefGoogle Scholar
  60. 60.
    Sakaguchi S, Sakaguchi N: Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease. J Exp Med 1990, 172:537–545.PubMedCrossRefGoogle Scholar
  61. 61.
    Fowell D, Mason D: Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med 1993, 177:627–636.PubMedCrossRefGoogle Scholar
  62. 62.
    Takayama T, Nishioka Y, Lu L, et al.: Retroviral delivery of viral interleukin-10 into myeloid dendritic cells markedly inhibits their allostimulatory activity and promotes the induction of Tcell hyporesponsiveness. Transplantation 1998, 66:1567–1574.PubMedCrossRefGoogle Scholar
  63. 63.
    Lee WC, Zhong C, Qian S, et al.: Phenotype, function, and in vivo migration and survival of allogeneic dendritic cell progenitors genetically engineered to express TGF-beta. Transplantation 1998, 66:1810–1817.PubMedCrossRefGoogle Scholar
  64. 64.
    Min WP, Gorczynski R, Huang XY, et al.: Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. J Immunol 2000, 164:161–167.PubMedGoogle Scholar
  65. 65.
    O'Rourke RW, Kang SM, Lower JA, et al.: A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival. Transplantation 2000, 69:1440–1446.PubMedCrossRefGoogle Scholar
  66. 66.
    Rea D, van Kooten C, van Meijgaarden KE, et al.: Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10. Blood 2000, 95:3162–3167.PubMedGoogle Scholar
  67. 67.
    Penna G, Adorini L: Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000, 164:2405–2411.PubMedGoogle Scholar
  68. 68.
    Lutz MB, Suri RM, Niimi M, et al.: Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol 2000, 30:1813–1822.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Alison Anne Cotterell
    • 1
  • Norma Sue Kenyon
    • 1
  1. 1.Diabetes Research InstituteUniversity of Miami School of MedicineMiamiUSA

Personalised recommendations