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

Abstract

OBJECTIVETo investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.RESEARCH DESIGN AND METHODSWe 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.RESULTSAutoantibodies 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.CONCLUSIONSWe 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.

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

“…Persistence of autoantibodies did not confer increased risk. While previous studies have noted associations of autoantibodies with graft failure 25, 29, our study is the first to link autoantibodies specifically to biopsy‐confirmed T1D recurrence, and in our own ongoing studies these are being linked to autoimmune T cell responses (Table S1A) 11, 42.…”

“…Forty‐seven patients (21.1%) developed posttransplant diabetes (HG group); 17 patients (7.6% overall, 36.2% of the HG group) had a clinical diagnosis of HG‐T1DR; this was confirmed by examination of a pancreas transplant biopsy in 15/17 (88%) patients, which demonstrated the presence of insulitis in 13/15 (87%) patients and significant loss of insulin staining in all (Table S1A) 11; thus, biopsy‐confirmed HG‐T1DR was found in 5.8% of our recipients (13/223). Although several of the patients had some biopsy evidence of coexisting pancreas rejection (Table S1B), this ranged from minimal to moderate in most with severe chronic rejection observed in a single patient (patient 5).…”

“…Later studies contributed evidence that recurrence of islet autoimmunity may occur regardless of HLA matching 18, 24 and despite immunosuppression 11, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 35. We initially reported 11 three patients in whom T1D recurrence was characterized by 1 hyperglycemia requiring insulin with impaired insulin secretion; 2 seroconversion of autoantibodies years prior to recurrence; 3 circulating autoreactive T cells around the time of diagnosis, often with simultaneous detection in pancreas transplant and associated lymph nodes; 4 insulitis and/or beta cell loss in the pancreas transplant biopsy, with no or minimal rejection; and 5 lack of laboratory evidence of rejection (unchanged urine amylase and serum creatinine levels).…”

“…With advances in immunosuppression, acute rejection has become less prevalent and immunological failures are typically ascribed to chronic rejection 8. However, another potential cause of immunological failure is T1D recurrence 11, 12. A growing literature suggests that islet autoimmunity may become reactivated and affect the endocrine function of pancreas transplants 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29.…”

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

“…Once the field eventually produces the functional equivalent of primary human pancreatic beta cells, a crucial obstacle will be to protect these cells from the stresses associated with transplantation, especially prior to complete engraftment, and recurrent autoimmunity in people with type 1 diabetes [12,65]. Some have argued that this will be impossible with fully functional beta cells, and that less mature products will be more robust at withstanding the stresses associated with transplantation and recurrent immunity.…”