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Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells

  • Author(s): Vendrame, F
  • Pileggi, A
  • Laughlin, E
  • Allende, G
  • Martin-Pagola, A
  • Molano, RD
  • Diamantopoulos, S
  • Standifer, N
  • Geubtner, K
  • Falk, BA
  • Ichii, H
  • Takahashi, H
  • Snowhite, I
  • Chen, Z
  • Mendez, A
  • Chen, L
  • Sageshima, J
  • Ruiz, P
  • Ciancio, G
  • Ricordi, C
  • Reijonen, H
  • Nepom, GT
  • Burke, GW
  • Pugliese, A
  • et al.

Published Web Location

https://doi.org/10.2337/db09-0498Creative Commons Attribution 4.0 International Public License
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 auto-antibodies 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 pretransplant 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 ∼1 year from hyperglycemia recurrence and revealed β-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), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed β-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 β-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used. © 2010 by the American Diabetes Association.

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