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Current Transplantation Reports

, Volume 5, Issue 4, pp 295–303 | Cite as

Type 1 Diabetes Recurrence After Simultaneous Pancreas-Kidney Transplantation

  • George W. Burke
  • Gaetano Ciancio
  • Mahmoud Morsi
  • Jose Figueiro
  • Linda Chen
  • Francesco Vendrame
  • Alberto Pugliese
Pancreas (D Axelrod and N Turgeon, Section Editors)
  • 18 Downloads
Part of the following topical collections:
  1. Topical Collection on Pancreas

Abstract

Purpose of Review

Simultaneous pancreas-kidney transplantation (SPKT) is an important option for patients with type 1 diabetes (T1D) and end-stage renal disease. While most SPKT recipients experience long-term euglycemia, about 5% return to insulin therapy, 5–20 years after transplantation due to T1D recurrence (T1DR). Over the last two decades, we have assessed autoimmunity in our patients, evaluating autoantibodies (GAD65, IA2, and ZnT8), autoreactive T cells, and pancreas transplant biopsies.

Recent Findings

Most patients demonstrate seroconversion for multiple autoantibodies. Autoreactive memory T cells have been identified in the peripheral blood, pancreas transplant, and peri-pancreas transplant tissues. Biopsies generally exhibit insulitis, the typical lesion of T1D, affecting pancreatic islets in the pancreas transplant, and lack of rejection in the pancreas and kidney transplants.

Summary

In addition to membrane expression of memory markers, we have identified other biomarkers, including CXCR3, on circulating and infiltrating autoreactive memory T cells. We hope that this work will lead to therapeutic intervention in our patients with T1DR, and that this will translate to effective treatment for T1D.

Keywords

Pancreas transplant Type 1 diabetes Autoimmunity Autoantibodies Autoreactive T cells Memory T cells 

Notes

Acknowledgements

The authors wish to acknowledge the John C. Hench Foundation for supporting this research in type 1 diabetes recurrence after simultaneous kidney-pancreas transplantation.

Compliance with Ethical Standards

Conflict of Interest

George Burke reports receiving research funds from the John C. Hench Foundation to support work on Type I Diabetes recurrence after kidney-pancreas transplantation. Francesco Vendrama, Gaetano Ciancio, Mahmoud Morsi, Jose Figueiro, Linda Chen, and Alberto Pugliese declare no conflict of interest.

Human and Animal Rights and Informed Consent

This is a review, however, we reference our own work for which we have institutional approval for animal and human research, and informed consents for human research.

References

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

  1. 1.
    Ciancio G, Sageshima J, Chen L, Gaynor JJ, Hanson L, Tueros L, et al. Advantage of rapamycin over mycophenolate mofetil when used with tacrolimus for simultaneous pancreas kidney transplants: randomized, single-center trial at ten years. Am J Transplant. 2012;12(12):3363–76.CrossRefGoogle Scholar
  2. 2.
    Finger EB, Radosevich DM, Dunn TB, Chinnakotla S, Sutherland DER, Matas AJ, et al. A composite risk model for predicting technical failure in pancreas transplantation. Am J Transplant. 2013;13:1840–9.  https://doi.org/10.1002/ajt.12269.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    •• Sutherland DER, Goetz FC, Sibley RK. Recurrence of disease in pancreas transplants. Diabetes. 1989;38(Supplement 1):85–7. This group described the first experience of recurrent autoimmunity in recipients of living donor partial pancreas transplants from twins or HLA identical siblings. CrossRefGoogle Scholar
  4. 4.
    Burke GWIII, Vendrame F, Virdi SK, Ciancio G, Chen L, Ruiz P, et al. Lessons from pancreas transplantation in type 1 diabetes: recurrence of islet autoimmunity. Curr Diab Rep. 2015;15(12):121.  https://doi.org/10.1007/s1.1892-015-0691-5.
  5. 5.
    Burke GWIII, Chen LJ, Ciancio G, Pugliese A. Biomarkers in pancreas transplant. Curr Opin Organ Transplant. 2016;21(4):412–8.  https://doi.org/10.1097/MOT.0000000000000333.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    •• Vendrame F, Hopfner Y, Diamantopoulos S, Virdi SK, Allende G, Snowhite IV, et al. Risk factors for type 1 diabetes recurrence in immunosuppressed recipients of simultaneous pancreas kidney transplants. Am J Transplant. 2016;16(1):235–45.  https://doi.org/10.1111/ajt.13426. This is the largest study of risk factors for T1DR after SPKT, demonstrating the importance of studying serial autoantibody levels.
  7. 7.
    Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473–9.CrossRefGoogle Scholar
  8. 8.
    Endsfelder D, Hagen M, Winkler C, Haupt F, Zillmer S, Knopff A, et al. A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children. Diabetologia. 2016;59:2172–80.  https://doi.org/10.1007/s00125-016-4050-0.
  9. 9.
    •• Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, 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;59:947–57. This paper demonstrated the occurrence of T1DR despite immunosuppression that prevents rejection; it also described in detail the timing of the clinical course of T1DR in relation to autoantibody levels, autoreactive T cell levels, pancreas transplant pathology, c-peptide levels, and therapeutic intervention of three patients. Google Scholar
  10. 10.
    Reijonen H, Geubtner K, Allende G, Kwok W, Nepom G, Burke 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(Supplement 1):A88.Google Scholar
  11. 11.
    Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new onset type 1 diabetes mellitus. New Engl J Med. 2002;346(22):1692–8.CrossRefGoogle Scholar
  12. 12.
    Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352(25):2598–608.CrossRefGoogle Scholar
  13. 13.
    Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Chéramy M, Pihl M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18):1909–20.  https://doi.org/10.1056/NEJMoa0804328.
  14. 14.
    Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143–52.  https://doi.org/10.1056/NEJMoa0904452.
  15. 15.
    Orban T, Bundy B, Becker DJ, DiMeglio L, Gitelman SE, Goland R, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomized, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):412–9.  https://doi.org/10.1016/S0140-6736(11)60886-6.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rigby MR, Harris KM, Pinckney A, DiMeglio LA, Rendell MS, Felner EI, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015;125(8):3285–96.CrossRefGoogle Scholar
  17. 17.
    Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol. 2005;23:447–85.CrossRefGoogle Scholar
  18. 18.
    Atkinson MA. Evaluating preclinical efficacy. Sci Transl Med. 2011;3:96cm22.CrossRefGoogle Scholar
  19. 19.
    Herold KC, Bluestone JA. Type 1 diabetes immunotherpy: is the glass half empty or half full? Sci Transl Med. 2011;3:95fs1.CrossRefGoogle Scholar
  20. 20.
    Xue S, Posgai A, Wasserfall C, Myhr C, Campbell-Thompson M, Mathews CE, et al. Combination therapy reverses hyperglycemia in NOD mice with established type 1 diabetes. Diabetes. 2015;64:3873–84.  https://doi.org/10.2337/db15-0164.
  21. 21.
    Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W, et al. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013;62(11):3766–74.  https://doi.org/10.2337/db13-0345.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    •• Pugliese A, Vendrame F, Reijonen H, Atkinson MA, Campbell-Thompson M, Burke GW. New insight on human type 1 diabetes biology: nPOD and nPOD-Transplantation. Curr Diab Rep. 2014;10:530.  https://doi.org/10.1007/s11892-014-0530-0. This paper reviews the important work of nPOD and nPOD-Transplantation. CrossRefGoogle Scholar
  23. 23.
    • Burke GW 3rd, Posgai AL, Wasserfall CH, Atkinson MA, Pugliese A. Raising awareness: the need to promote allocation of pancreata from rare nondiabetic donors with pancreatic islet autoimmunity to type1 diabetes research. Am J Transplant. 2017;17(1):306–7.  https://doi.org/10.1111/ajt.13983. This paper approaches the pancreas transplant community with a key request to permit the study of autoantibody-positive, non-diabetic pancreas donors for research. CrossRefPubMedGoogle Scholar
  24. 24.
    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.  https://doi.org/10.1016/j.clim.2008.03.459.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Elyoussfi S, Thomas BJ, Ciurtin C. Tailored treatment options for patients with psoriatic arthritis and psoriasis: review of established and new biologic and small molecule therapies. Rheumatol Int. 2016;36(5):603–12.  https://doi.org/10.1007/s00296-016-3436-0.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Pugliese A, Reijonen H, Vendrame F, Werra G, Allende G, Hanson L, et al. Treatment of recurrent islet autoimmunity in a pancreas transplant recipient with alefacept. 13th Meeting of the Immunology of Diabetes Society, Australia, Abstract Book, December 2013.Google Scholar
  27. 27.
    Marwaha AK, Tan S, Dutz JP. Targeting the IL-17/IFN-gamma axis as a potential new clinical therapy for type 1 diabetes. Clin Immunol. 2014;154:84–9.  https://doi.org/10.1016/j.clim.2014.06.006.CrossRefPubMedGoogle Scholar
  28. 28.
    Papp KA, Blauvelt A, Bukhalo M, Gooderham M, Krueger JG, Lacour JP, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376(16):1551–60.  https://doi.org/10.1056/NEJMoa1607017.CrossRefPubMedGoogle Scholar
  29. 29.
    Reijonen H, Werra G, Falk, et al. Association of autoreactive memory CD4 T cells expressing the chemokine receptor CXCR3 in the peripheral blood of pancreas-kidney transplant recipients with type 1 diabetes recurrence. Presented at the Immunology of Diabetes Society Meeting, San Francisco, January 2017.Google Scholar
  30. 30.
    Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Holländer GA, et al. Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med. 2002;8(12):1414–20.  https://doi.org/10.1038/nm792.CrossRefPubMedGoogle Scholar
  31. 31.
    Dai Z, Xing L, Cerise J, Wang EHC, Jabbari A, de Jong A, et al. CXCR3 blockade inhibits T cell migration into the skin and prevents development of alopecia areata. J Immunol. 2016;197(4):1089–99.  https://doi.org/10.4049/jimmunol.1501798.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jabbari A, Cerise JE, Chen JC, Mackay-Wiggan J, Duvic M, Price V, et al. Molecular signatures define alopecia areata and transcriptional biomarkers. EBioMedicine. 2016;7:240–7.  https://doi.org/10.1016/j.ebiom.2016.03.036.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lenchik NI, Dahl-Jorgensen K, Burke GW, Krogvold L, Pugliese A, Mathews CE, et al. Gene expression profiles of human islets with ongoing autoimmunity and type 1 diabetes. Presented at the 75th Annual Meeting of American Diabetes Association. Diabetes. 2015;64(suppl. 1):A468.Google Scholar
  34. 34.
    Shreberk-Hassidim R, Ramot Y, and Zlotogorski A. Janus kinase inhibitors in dermatology: a systematic review. J Am Acad Dermatol. 2017.  https://doi.org/10.1016/j.jaad.2016.12.004.
  35. 35.
    Jabbari A, Zhenpeng D, Luzhou X, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of alopecia areata following treatment with the JAK 1,2 inhibitor baricitinib. EBioMedicine. 2015;2:351–5.Google Scholar
  36. 36.
    O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36:542–50.CrossRefGoogle Scholar
  37. 37.
    Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, et al. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016;1(15):e89776.CrossRefGoogle Scholar
  38. 38.
    Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, et al. Oral ruxolitinib induces hair growth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1(15):e89790.CrossRefGoogle Scholar
  39. 39.
    Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, et al. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015;125(1):448–55.  https://doi.org/10.1172/JCI78492.CrossRefPubMedGoogle Scholar
  40. 40.
    Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Perry DJ, Schultz AR, et al. Antithymocyte globulin plus G-CSF combination therapy leads to sustained immunomodulatory and metabolic effects in a subset of responders with established type 1 diabetes. Diabetes. 2016;65:3765–75.  https://doi.org/10.2337/db16-0823.
  41. 41.
    Haller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, et al. Low-dose anti-thymocyte globulin (ATG) preserves beta-cell function and improves HbA1c in new-onset type 1 diabetes. Diabetes Care. 2018;41:1917–25.  https://doi.org/10.2337/dc18-0494.CrossRefPubMedGoogle Scholar
  42. 42.
    Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, et al. ITN START study team. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomized trial. Diabetologia. 2016;59(6):1153–61.  https://doi.org/10.1007/s00125-016-3917-4.
  43. 43.
    •• Skyler JS. Prevention and reversal of type1 diabetes – past challenges and future opportunities. Diabetes Care. 2015;38:997–1007.  https://doi.org/10.2337/dc15-0349. This article highlights the possible combination of therapeutic options most likely to be implemented with success for T1D in the future. CrossRefPubMedGoogle Scholar
  44. 44.
    Blair HA. Dimethyl fumarate: a review in moderate to severe plaque psoriasis. Drugs. 2018;78(1):123–30.  https://doi.org/10.1007/s40265-017-0854-6.CrossRefPubMedGoogle Scholar
  45. 45.
    Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y. Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front Neurol. 2018;9(5):1–8.  https://doi.org/10.3389/fneur.2018.00005.CrossRefGoogle Scholar
  46. 46.
    Cunill V, Massot M, Clemente A, Calles C, Andreu V, Núñez V, et al. Relapsing-remitting multiple sclerosis is characterized by a T follicular cell pro-inflammatory shift, reverted by dimethyl fumarate treatment. Front Immunol. 2018;9:1097.  https://doi.org/10.3389/fimmu.2018.01097.ECollection.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med. 1985;313(6):353–60.CrossRefGoogle Scholar
  48. 48.
    Pugliese A. Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes. 2016;17(Suppl 22):31–6.  https://doi.org/10.1111/pedi.12388.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, et al. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes. 2016;65(3):719–31.  https://doi.org/10.2337/db15-0779.CrossRefPubMedGoogle Scholar
  50. 50.
    Brozzi F, Eizirik DL. ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes. Ups J Med Sci. 2016;121(2):133–9.  https://doi.org/10.3109/03009734.2015.1135217.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Nagy N, Kaber G, Johnson PY, Gebe JA, Preisinger A, Falk BA, et al. Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. J Clin Invest. 2015;125(10):3928–40.  https://doi.org/10.1172/JCI179271.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • George W. Burke
    • 1
    • 2
    • 3
  • Gaetano Ciancio
    • 1
    • 2
  • Mahmoud Morsi
    • 1
    • 2
  • Jose Figueiro
    • 1
    • 2
  • Linda Chen
    • 1
    • 2
  • Francesco Vendrame
    • 4
  • Alberto Pugliese
    • 3
    • 4
    • 5
  1. 1.Miami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Department of Surgery, Division of TransplantationUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Diabetes Research InstituteUniversity of Miami Miller School of MedicineMiamiUSA
  4. 4.Department of Medicine, Division of Endocrinology, Diabetes and MetabolismUniversity of Miami Miller School of MedicineMiamiUSA
  5. 5.Department of Microbiology and ImmunologyUniversity of Miami Miller School of MedicineMiamiUSA

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