Recurrence of Type 1 Diabetes After Simultaneous Pancreas-Kidney Transplantation, Despite Immunosuppression, Is Associated With Autoantibodies and Pathogenic Autoreactive CD4 T-Cells

  1. Alberto Pugliese1,5,6
  1. 1Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida;
  2. 2Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, Florida;
  3. 3Benaroya Research Institute, Seattle, Washington;
  4. 4Clinical Immunology, Amgen Inc., Seattle, Washington;
  5. 5Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, Florida;
  6. 6Department of Medicine, Division of Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, Florida.
  1. Corresponding author: Alberto Pugliese, apuglies{at}med.miami.edu.
  1. F.V. and A.Pi. contributed equally to this work. G.W.B. and A.Pu. were co-principal investigators and contributed equally to this work.

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 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.

Footnotes

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

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  1. Diabetes vol. 59 no. 4 947-957
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