Current Diabetes Reports

, Volume 11, Issue 5, pp 413–419 | Cite as

Recurrence of Autoimmunity Following Pancreas Transplantation

  • George W. BurkeIII
  • Francesco Vendrame
  • Antonello Pileggi
  • Gaetano Ciancio
  • Helena Reijonen
  • Alberto Pugliese


Pancreas transplantation is a therapeutic option for patients with type 1 diabetes. Advances in immunosuppression have reduced immunologic failures, and these are usually categorized as chronic rejection. Yet studies in our cohort of pancreas transplant recipients identified several patients in whom chronic islet autoimmunity led to recurrent diabetes, despite immunosuppression that prevented rejection. Recurrent diabetes in our cohort is as frequent as chronic rejection, and thus is a significant cause of immunologic graft failure. Our studies demonstrated islet autoimmunity by the presence of autoantibodies and autoreactive T cells, which mediated ß-cell destruction in a transplantation model. Biopsy of the transplanted pancreas revealed variable degrees of ß-cell loss, with or without insulitis, in the absence of pancreas and kidney transplant rejection. Additional research is needed to better understand recurrent disease and to identify new treatment regimens that can suppress autoimmunity, as in our experience this is not effectively inhibited by conventional immunosuppression.


Type 1 diabetes Pancreas transplantation Recurrent diabetes Autoimmunity GAD65 Autoantibodies 


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

  1. 1.
    White SA, Shaw JA, Sutherland DE. Pancreas transplantation. Lancet. 2009;373(9677):1808–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Sageshima J, Ciancio G, Gaynor JJ, et al. Addition of anti-CD25 to thymoglobulin for induction therapy: delayed return of peripheral blood CD25-positive population. Clin Transplant. 2011;25(2):E132–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Neidlinger N, Singh N, Klein C, et al. Incidence of and risk factors for posttransplant diabetes mellitus after pancreas transplantation. Am J Transplant. 2010;10(2):398–406.PubMedCrossRefGoogle Scholar
  4. 4.
    Dean PG, Kudva YC, Larson TS, Kremers WK, Stegall MD. Posttransplant diabetes mellitus after pancreas transplantation. Am J Transplant. 2008;8(1):175–82.PubMedGoogle Scholar
  5. 5.
    Sutherland DE, Sibley R, Xu XZ, et al. Twin-to-twin pancreas transplantation: reversal and reenactment of the pathogenesis of type I diabetes. Trans Assoc Am Physicians. 1984;97:80–7.PubMedGoogle Scholar
  6. 6.
    Sibley RK, Sutherland DE, Goetz F, Michael AF. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest. 1985;53(2):132–44.PubMedGoogle Scholar
  7. 7.
    Sutherland DE, Goetz FC, Sibley RK. Recurrence of disease in pancreas transplants. Diabetes. 1989;38(S1):85–7.PubMedGoogle Scholar
  8. 8.
    Tyden G, Reinholt FP, Sundkvist G, Bolinder J. Recurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts. N Engl J Med. 1996;335(12):860–3.PubMedCrossRefGoogle Scholar
  9. 9.
    Santamaria P, Nakhleh RE, Sutherland DE, Barbosa JJ. Characterization of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes. 1992;41(1):53–61.PubMedCrossRefGoogle Scholar
  10. 10.
    • Vendrame F, Pileggi A, Laughlin E et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 2010;59(4):947–57. This article is the original source for much of the data reviewed in this article.PubMedCrossRefGoogle Scholar
  11. 11.
    • Ishida-Oku M, Iwase M, Sugitani A et al. A case of recurrent type 1 diabetes mellitus with insulitis of transplanted pancreas in simultaneous pancreas-kidney transplantation from cardiac death donor. Diabetologia 2010; 53(2):341–5. This article identified another case of recurrent diabetes in an immunosuppressed patient.PubMedCrossRefGoogle Scholar
  12. 12.
    Sibley RK, Sutherland DE. Pancreas transplantation. An immunohistologic and histopathologic examination of 100 grafts. Am J Pathol. 1987;128(1):151–70.PubMedGoogle Scholar
  13. 13.
    Bosi E, Bottazzo GF, Secchi A, et al. Islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation. Diabetes. 1989;38(S1):82–4.PubMedGoogle Scholar
  14. 14.
    Esmatjes E, Rodriguez-Villar C, Ricart MJ, et al. Recurrence of immunological markers for type 1 (insulin-dependent) diabetes mellitus in immunosuppressed patients after pancreas transplantation. Transplantation. 1998;66(1):128–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Petruzzo P, Andreelli F, McGregor B, et al. Evidence of recurrent type I diabetes following HLA-mismatched pancreas transplantation. Diabetes Metab. 2000;26(3):215–8.PubMedGoogle Scholar
  16. 16.
    Thivolet C, Abou-Amara S, Martin X, et al. Serological markers of recurrent beta cell destruction in diabetic patients undergoing pancreatic transplantation. Transplantation. 2000;69(1):99–103.PubMedCrossRefGoogle Scholar
  17. 17.
    Braghi S, Bonifacio E, Secchi A, et al. Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes. 2000;49(2):218–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Hilbrands R, Huurman VA, Gillard P, et al. Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes. 2009;58(10):2267–76.PubMedCrossRefGoogle Scholar
  19. 19.
    Huurman VA, Hilbrands R, Pinkse GG, et al. Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS One. 2008;3(6):e2435.PubMedCrossRefGoogle Scholar
  20. 20.
    Diamantopoulos S, Allende G, Martin-Pagola A, et al. Recurrence of type 1 diabetes (T1DR) after simultaneous pancreas-kidney (SPK) transplantation is associated with islet cell autoantibody conversion. Acta Diabetol. 2007;44(S1):S13.Google Scholar
  21. 21.
    Sundkvist G, Tyden G, Karlsson FA, Bolinder J. Islet autoimmunity before and after pancreas transplantation in patients with Type I diabetes mellitus. Diabetologia. 1998;41(12):1532–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Laughlin E, Burke G, Pugliese A, Falk B, Nepom G. Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation. Clin Immunol. 2008;128(1):23–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Reijonen H, Geubtner K, Allende G, et al. Identification of islet-autoantigen specific CD4+ T-cells in the pancreatic lymph nodes and pancreas of a pancreas-kidney transplant patient with recurrence of autoimmunity. Diabetes. 2006;55(S1):88A.Google Scholar
  24. 24.
    Tsai EB, Sherry NA, Palmer JP, Herold KC. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia. 2006;49:261–70.PubMedCrossRefGoogle Scholar
  25. 25.
    Smukler SR, Arntfield ME, Razavi R, et al. The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell. 2011;8(3):281–93.PubMedCrossRefGoogle Scholar
  26. 26.
    Bonner-Weir S, Li WC, Ouziel-Yahalom L, et al. Beta-cell growth and regeneration: replication is only part of the story. Diabetes. 2010;59(10):2340–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Keenan HA, Sun JK, Levine J, et al. Residual insulin production and pancreatic beta-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 2010;59(11):2846–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Meier JJ, Butler AE, Saisho Y, et al. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes. 2008;57(6):1584–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Butler PC, Meier JJ, Butler AE, Bhushan A. The replication of beta cells in normal physiology, in disease and for therapy. Nat Clin Pract Endocrinol Metab. 2007;3(11):758–68.PubMedCrossRefGoogle Scholar
  30. 30.
    Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia. 2005;48(11):2221–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Melmed RN, Benitez CJ, Holt SJ. Intermediate cells of the pancreas. I. Ultrastructural characterization. J Cell Sci. 1972;11(2):449–75.PubMedGoogle Scholar
  32. 32.
    Yatoh S, Dodge R, Akashi T, et al. Differentiation of affinity-purified human pancreatic duct cells to beta-cells. Diabetes. 2007;56(7):1802–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Meier JJ, Ritzel RA, Maedler K, Gurlo T, Butler PC. Increased vulnerability of newly forming beta cells to cytokine-induced cell death. Diabetologia. 2005;49:83–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Juhl K, Bonner-Weir S, Sharma A. Regenerating pancreatic beta-cells: plasticity of adult pancreatic cells and the feasibility of in-vivo neogenesis. Curr Opin Organ Transplant. 2010;15(1):79–85.PubMedCrossRefGoogle Scholar
  35. 35.
    Martin-Pagola A, Sisino G, Allende G, et al. Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity. Diabetologia. 2008;51(10):1803–13.PubMedCrossRefGoogle Scholar
  36. 36.
    Jonsson J, Ahlgren U, Edlund T, Edlund H. IPF1, a homeodomain protein with a dual function in pancreas development. Int J Dev Biol. 1995;39(5):789–98.PubMedGoogle Scholar
  37. 37.
    Tanaka S, Kobayashi T, Nakanishi K, et al. Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis. Diabetes Care. 2001;24(9):1661–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Bottino R, Criscimanna A, Casu A, et al. Recovery of endogenous beta-cell function in nonhuman primates after chemical diabetes induction and islet transplantation. Diabetes. 2009;58(2):442–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Wang GS, Rosenberg L, Scott FW. Tubular complexes as a source for islet neogenesis in the pancreas of diabetes-prone BB rats. Lab Invest. 2005;85(5):675–88.PubMedCrossRefGoogle Scholar
  40. 40.
    Kauri LM, Wang GS, Patrick C, et al. Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats. Lab Invest. 2007;87(12):1240–51.PubMedCrossRefGoogle Scholar
  41. 41.
    Xu X, D’Hoker J, Stange G, et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008;132(2):197–207.PubMedCrossRefGoogle Scholar
  42. 42.
    Xia B, Zhan XR, Yi R, Yang B. Can pancreatic duct-derived progenitors be a source of islet regeneration? Biochemistry Biophysics Res Commun. 2009;383(4):383–5.CrossRefGoogle Scholar
  43. 43.
    Jarchum I, Nichol L, Trucco M, Santamaria P, DiLorenzo TP. Identification of novel IGRP epitopes targeted in type 1 diabetes patients. Clin Immunol. 2008;127(3):359–65.PubMedCrossRefGoogle Scholar
  44. 44.
    Unger WW, Pinkse GG, der Mulder-van KS, et al. Human clonal CD8 autoreactivity to an IGRP islet epitope shared between mice and men. Ann N Y Acad Sci. 2007;1103:192–5.PubMedCrossRefGoogle Scholar
  45. 45.
    King C, Ilic A, Koelsch K, Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004;117(2):265–77.PubMedCrossRefGoogle Scholar
  46. 46.
    Viglietta V, Kent SC, Orban T, Hafler DA. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J Clin Invest. 2002;109(7):895–903.PubMedGoogle Scholar
  47. 47.
    Monti P, Scirpoli M, Rigamonti A, et al. Evidence for in vivo primed and expanded autoreactive T cells as a specific feature of patients with type 1 diabetes. J Immunol. 2007;179(9):5785–92.PubMedGoogle Scholar
  48. 48.
    Monti P, Heninger AK, Bonifacio E. Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus. Curr Diab Rep. 2009;9(2):113–8.PubMedCrossRefGoogle Scholar
  49. 49.
    • Monti P, Scirpoli M, Maffi P et al. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J. Clin. Invest. 2008;118(5):1806–14. This article provides evidence for a role of memory cells in patients with islet cell transplants.PubMedGoogle Scholar
  50. 50.
    Matthews JB, Staeva TP, Bernstein PL, Peakman M. von HM. Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group. Clin Exp Immunol. 2010;160(2):176–84.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • George W. BurkeIII
    • 1
  • Francesco Vendrame
    • 2
  • Antonello Pileggi
    • 3
  • Gaetano Ciancio
    • 4
  • Helena Reijonen
    • 5
  • Alberto Pugliese
    • 6
  1. 1.Department of Surgery, Division of Transplantation, Leonard Miller School of MedicineUniversity of MiamiMiamiUSA
  2. 2.Diabetes Research Institute, Leonard Miller School of MedicineUniversity of MiamiMiamiUSA
  3. 3.Diabetes Research Institute and Department of SurgeryLeonard Miller School of Medicine, University of MiamiMiamiUSA
  4. 4.Department of Urology, Department of Surgery, Division of Transplantation, Leonard Miller School of MedicineUniversity of MiamiMiamiUSA
  5. 5.Benaroya Research InstituteSeattleUSA
  6. 6.Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of MIcrobiology and ImmunologyDiabetes Research Institute, Leonard Miller School of Medicine, University of MiamiMiamiUSA

Personalised recommendations