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Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.

ABSTRACT: To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.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.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.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.

SUBMITTER: Vendrame F

PROVIDER: S-EPMC2844842 | biostudies-other | 2010 Apr

REPOSITORIES: biostudies-other

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Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.

Vendrame Francesco F 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

Diabetes 20100119 4

<h4>Objective</h4>To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.<h4>Research design and methods</h4>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.<h4>Results</h4>Autoantibodies were present pretransplant and persisted on follow-up in one patient. The ...[more]

PMID: 20086230

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Project description:Pancreatic autoantibodies (AAb) has been associated with a worse pancreas graft survival after simultaneous pancreas-kidney transplantation (SPK). However, due to the variable time for AAb to become positive and the lack of early biomarkers suggesting such autoimmune activation, the mechanisms leading ß-cell destruction remain uncertain. The present study aimed to evaluate the association between post-transplant AAb and the functional impairment of the pancreatic ß-cell and also the association of such AAb with inflammation after SPK. In a longitudinal study, we analyzed the impact of post-transplant glutamic acid decarboxylase (GAD-65) and the insulinoma-associated autoantigen 2 (IA-2) AAb on pancreas graft function. Serum Hb1Ac and C-peptide (C-pep) were longitudinally compared between a group with positive posttransplant AAb (AAb+; n = 40) and another matched group with negative AAb (AAb-; n = 40) until the fifth year following seroconversion. In the cross-sectional analysis, we further evaluated the systemic signatures of inflammation by measuring pro-inflammatory CD14+CD16+ monocytes by flow-cytometry and interleukin 17-A serum levels in 38 SPK recipients and ten healthy controls. In the longitudinal study, patients with AAb+ showed higher levels of Hb1Ac (p<0.001) and lower C-pep levels (p<0.001) compared to those who remained AAb- throughout the follow-up. In the cross-sectional study, AAb+ patients showed a higher percentage of CD14+CD16+ monocytes compared with those with AAb- and the healthy controls (6.70±4.19% versus 4.0±1.84% and 3.44±0.93%; p = 0.026 and 0.009 respectively). Also, CD14+CD16+ monocytes correlated with Hb1Ac and C-pep serum levels. Multivariate logistic regression showed that posttransplant AAb+ was independently associated with a higher percentage of pro-inflammatory monocytes (adjusted-OR 1.59, 95%CI 1.05-2.40, p = 0.027). The group of patients with positive AAb also showed higher levels of IL17A as compared with the other groups (either healthy control or the negative AAb subjects). In conclusion, pancreatic AAb+ after SPK were not only associated with higher Hb1Ac and lower c-peptide serum levels but also with an increased percentage of CD14+CD16+ monocytes and higher levels of circulating IL17-A.

Project description:BackgroundPancreas transplant alone (PTA) recipients are more affected by pancreas graft thrombosis, and graft loss compared to simultaneous pancreas-kidney (SPK) recipients. The pathophysiology is unknown, but an increased immune response has been suggested in the PTA recipients. In this observational study, we compared perioperative thromboinflammation between PTA (n=32) and SPK (n=35) recipients, and between PTA recipients with (n=14) versus without (n=18) early graft thrombosis.MethodsWe measured C-reactive protein (CRP), plasma markers of activated coagulation and complement, and cytokines preoperatively and daily during the first postoperative week.ResultsPreoperatively, coagulation and complement activation markers were comparable between PTA and SPK recipients, while cytokine concentrations were higher in SPK recipients (TNF, IL-8, IP-10, MCP-1, MIP-1α; all p<0.05). On the first postoperative day, PTA recipients had higher coagulation activation, measured as thrombin-antithrombin complex (TAT), than SPK recipients (p=0.008). In the first postoperative week, PTA recipients showed higher relative cytokine release (IL-6, IL-8, G-CSF, IP-10, MCP-1, and MIP-1α; all p<0.05) while SPK recipients showed higher absolute cytokine concentrations (TNF, IL-1ra, IL-8, MIP-1α, and IL-4; all p<0.05). PTA and SPK recipients showed similar terminal complement complex (TCC, sC5b-9) activation. On the first postoperative day, TCC (OR 1.2 [95% CI 1.0-1.5] for 0.1 CAU/ml increase, p=0.02) and CRP (OR 1.2 [95% CI 1.0-1.3] for 10 mg/L increase, p=0.04) were associated with an increased risk of early graft thrombosis. TCC was specific for graft thrombosis, while CRP increased with several complications. PTA recipients with compared to those without graft thrombosis had higher TCC pre- (p=0.04) and postoperatively (p=0.03).ConclusionThe relative increase in postoperative thromboinflammatory response was more pronounced in PTA recipients. Complement activation was associated with an increased risk of graft thrombosis. This study indicates that innate immune activation rather than elevated levels may affect early postoperative pancreas graft thrombosis.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT01957696, identifier NCT01957696.

Dataset Information

Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.

Publications

Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.

Similar Datasets

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