Recurrence of Type 1 Diabetes after Simultaneous Pancreas-Kidney Transplantation, despite Immunosuppression, Associated with Autoantibodies and Pathogenic Autoreactive CD4 T-cells

  1. Francesco Vendrame1,
  2. Antonello Pileggi1,2,
  3. Elsa Laughlin5,
  4. Gloria Allende1,
  5. Ainhoa Martin-Pagola1,
  6. R. Damaris Molano1,
  7. Stavros Diamantopoulos1,
  8. Nathan Standifer5,6,
  9. Kelly Geubtner5,
  10. Ben A. Falk5,
  11. Hirohito Ichii1,2,
  12. Hidenori Takahashi2,
  13. Isaac Snowhite1,
  14. Zhibin Chen4,
  15. Armando Mendez1,3,
  16. Linda Chen2,
  17. Junichiro Sageshima2,
  18. Phillip Ruiz2,
  19. Gaetano Ciancio2,
  20. Camillo Ricordi1,2,3,4,
  21. Helena Reijonen5,
  22. Gerald T. Nepom5,
  23. George W. Burke III1,2 and
  24. Alberto Pugliese (apuglies{at}med.miami.edu)1,3,4
  1. 1Diabetes Research Institute
  2. 2Department of Surgery, Division of Transplantation
  3. 3Department of Medicine, Division of Endocrinology and Metabolism
  4. 4Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, Florida, 33136
  5. 5Benaroya Research Institute, Seattle, Washington, 98101
  6. 6Clinical Immunology, Amgen Inc., Seattle, Washington

Abstract

Objective: to investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed, simultaneous pancreas-kidney (SPK) transplant recipients.

Research Design and Methods: we monitored autoantibodies and autoreactive T-cells (using tetramers), and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays.

Results: autoantibodies were present pre-transplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately one year from hyperglycemia recurrence and revealed ß-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell directed therapy (rituximab, two patients) non-specifically depleted T-cells and was associated with C-peptide secretion for over one year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next two years. Purified autoreactive CD4 T-cells from two patients were co-transplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed ß-cell loss in mice receiving autoreactive T-cells but not control T-cells.

Conclusions: We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating ß-cell destruction. Markers of autoimmunity can help diagnose this under-appreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents utilized.

Footnotes

    • Received April 3, 2009.
    • Accepted January 6, 2010.

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  1. Diabetes
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