title: Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.
abstract: OBJECTIVE
  To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.
  
  
  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 approximately 1 year from hyperglycemia recurrence and revealed beta-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 beta-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 beta-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.
authors.affiliation: Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vendrame
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Elsa
authors.initials: E
authors.lastname: Laughlin
authors.forename: Gloria
authors.initials: G
authors.lastname: Allende
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Martin-Pagola
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.forename: Stavros
authors.initials: S
authors.lastname: Diamantopoulos
authors.forename: Nathan
authors.initials: N
authors.lastname: Standifer
authors.forename: Kelly
authors.initials: K
authors.lastname: Geubtner
authors.forename: Ben A
authors.initials: BA
authors.lastname: Falk
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ichii
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
authors.forename: Isaac
authors.initials: I
authors.lastname: Snowhite
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Chen
authors.forename: Armando
authors.initials: A
authors.lastname: Mendez
authors.forename: Linda
authors.initials: L
authors.lastname: Chen
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sageshima
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Gaetano
authors.initials: G
authors.lastname: Ciancio
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Helena
authors.initials: H
authors.lastname: Reijonen
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.forename: Alberto
authors.initials: A
authors.lastname: Pugliese
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D015551:Autoimmunity; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000601:surgery*; D003928:Diabetic Nephropathies / Q000276:immunology / Q000601:surgery; D005260:Female; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D016035:Pancreas Transplantation / Q000276:immunology / Q000473:pathology*; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies