Abstract
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.
Highlights
Type 1 Diabetes (T1D) is an autoimmune and inflammatory disease associated with the destruction of pancreatic insulin-producing ß-cells [1,2,3,4]
We further performed a cross-sectional study in a cohort of patients in whom pancreas and kidney graft function were considered within the normal range at the time of inclusion: fasting plasma glucose 0.20 pmol/mL), non-requirement of exogenous insulin and glomerular filtration rate (GFR) >60 mL/min/1.73m2 estimated by MDRD-4 (S2 Dataset)
Inflammatory parameters such as albumin, ferritin, and high-sensitivity C-reactive protein and parameters associated with pancreas graft function such as fasting glucose, Cpep by radioimmunoassay (Izotop Bioassays, Budapest, Hungary) and fasting plasma insulin were analyzed at the time of blood drawn
Summary
Type 1 Diabetes (T1D) is an autoimmune and inflammatory disease associated with the destruction of pancreatic insulin-producing ß-cells [1,2,3,4]. A disequilibrium between effectors T-cells and Tregs may be associated with the onset of ß-cell function decline; auto-reactive T-cells are determinant in this expanding autoimmune process [1,9]. In this line, the Th1 IFNy-producing cells and the Th17 IL-17-producing cells are closely related to autoimmunity [10]. IL-17 modulates the traffic of different immune cells such as monocytes [10,13]. Recruitment and differentiation of monocytes together with the IL-17 cytokine [15] are both implicated in the immune process preceding T1D
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