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

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FIG. 3.
FIG. 3.

Clinical course, autoimmunity assessment, and biopsy in patient 3. Patient 3 is a 38-year-old Caucasian male [HLA A26/A30, B38/B58, DR3/DR4 (DRB1*0402)] who developed type 1 diabetes at age 12 years. He received an SPK transplant from an HLA-A23/A33, B7/B52, DR2/DR10 donor at age 27 years. The pancreas transplant successfully reversed diabetes. Five years later, the patient developed hyperglycemia requiring insulin therapy with unchanged function of the kidney and exocrine pancreas allografts. A: Autoantibody levels before transplant and on follow-up. Color-matched blue and black horizontal lines represent cutoffs for GAD/IA-2 and ZnT8 autoantibodies, respectively. The patient had been autoantibody negative before transplant and for almost 5 years on follow-up, but converted to GAD and ZnT8 autoantibody positivity about 3 months before the recurrence of hyperglycemia. At the time, there was a sharp rise in ZnT8 autoantibodies, shortly thereafter followed by a similar rise in GAD autoantibody levels, peaking at levels that were 40-fold and 10-fold higher than the upper limit of normal, respectively. Inset: Hormone stains in the first pancreas transplant biopsy obtained at retransplantation demonstrate β-cell loss. B: Serum C-peptide levels and % of GAD tetramer–positive T-cells in the CD4 T-cell population from the time of hyperglycemia recurrence. Patient 3 had no residual C-peptide secretion in the fasting state and no response to a Sustacal meal test (not shown) at the onset of hyperglycemia. C-peptide secretion was restored by retransplantation but was lost again after rejection of the second pancreas transplant. GAD-specific autoreactive CD4 T-cells were first studied in the sample obtained before the immunosuppression required for the second transplant. Autoreactive T-cells became undetectable after immunosuppression, but eventually rebounded and were detected on multiple occasions. The horizontal blue line represents the cutoff of the tetramer assay (0.25%). C: Flow cytometry plots demonstrating strong responses of GAD autoreactive, CD4 T-cells. Numbers above the plots correspond to those in B. Tetramer staining with irrelevant peptide was <0.1% (not shown). D: Biopsy of the second pancreas graft showing rejection. CD4 infiltrates are seen near residual insulin-stained areas. DM, diabetes; Tx, treatment. (A high-quality digital representation of this figure is available in the online issue.)

This Article

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