Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.
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.
Vendrame
Francesco
F
Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA.
Pileggi
Antonello
A
Laughlin
Elsa
E
Allende
Gloria
G
Martin-Pagola
Ainhoa
A
Molano
R Damaris
RD
Diamantopoulos
Stavros
S
Standifer
Nathan
N
Geubtner
Kelly
K
Falk
Ben A
BA
Ichii
Hirohito
H
Takahashi
Hidenori
H
Snowhite
Isaac
I
Chen
Zhibin
Z
Mendez
Armando
A
Chen
Linda
L
Sageshima
Junichiro
J
Ruiz
Phillip
P
Ciancio
Gaetano
G
Ricordi
Camillo
C
Reijonen
Helena
H
Nepom
Gerald T
GT
Burke
George W
GW
Pugliese
Alberto
A
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
D001323:Autoantibodies