Development of immune response to tissue‐restricted self‐antigens in simultaneous kidney‐pancreas transplant recipients with acute rejection

Abstract

Simultaneous kidney-pancreas transplantation (SKP Tx) is a treatment for end-stage kidney disease secondary to diabetes mellitus. We investigated the role of immune responses to donor human leukocyte antigens (HLA) and tissue-restricted kidney and pancreas self-antigens (KSAgs and PSAgs, respectively) in SKP Tx recipients (SKP TxRs). Sera collected from 39 SKP TxRs were used to determine de novo Abs specific for KSAgs (collagen-IV, Col-IV; fibronectin, FN) and PSAgs (insulin, islet cells, glutamic acid decarboxylase, and pancreas-associated protein-1) by ELISA. KSAg-specific IFN-γ, IL-17, and IL-10 cytokines were enumerated by ELISpot. Abs to donor HLA classes I and II were determined by Luminex assay. Abs to KSAgs and PSAgs were detectable in recipients with rejection compared with stable recipients (P<.05). Kidney-only rejection recipients had increased Abs against KSAgs compared with stable (P<.05), with no increase in Abs against PSAgs. Pancreas-only rejection recipients showed increased Abs against PSAgs compared to stable (P<.05), with no Abs against KSAgs. SKP TxRs with rejection showed increased frequencies of KSAg-specific IFN-γ and IL-17 with reduction in IL-10-secreting cells. SKP TxRs with rejection developed Abs to KSAgs and PSAgs demonstrated increased frequencies of kidney or pancreas SAg-specific IFN-γ and IL-17-secreting cells with reduced IL-10, suggesting loss of peripheral tolerance to SAgs.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…Finally, development of antibodies directed against tissue-specific self-antigens, such as Fibronectin (FN) and Collagen type IV (Col IV), increases the risk of AR in pancreas-kidney transplantation (PKT) [ 135 ] and transplant glomerulopathy in KTx [ 136 ]. These autoantibodies probably reflect breakdown of tolerance towards self-antigens, as suggested by detection of self-Ag-specific IFN-γ and IL-17 secreting T-cells in the same patients.…”

Functional and immunological peculiarities of peripheral nerve allografts

“…The host immune response to transplanted tissues Rejection of transplanted tissue is generally initiated by a local innate inflammatory response that potentiates a subsequent adaptive response (Gunasekaran et al, 2017). Macrophages and resident dendritic cells promote inflammation and help recruit adaptive immune cells, such as T cells, to release inflammatory cytokines, chemokines and reactive oxidative species that exacerbate tissue damage (Muller et al, 2006;Gunasekaran et al, 2017). Macrophages and dendritic cells acting as antigen presenting cells (APCs) further activate T cells to specifically target the grafted tissue.…”

Epidemiological profile of the pancrêas-rim transplant and analysis of the immunological markers of rejection

“…As citocinas IFN-γ, IL-17 e IL-10 específicas da KSAg foram enumeradas pelo ELISpot. Os receptores de rejeição somente para rins aumentaram o Abs contra os KSAgs em comparação com os estáveis, sem aumento de Abs contra PSAgs(Gunasekaran, 2017).Os beneficiários da rejeição apenas com pâncreas apresentaram aumento do Abs contra PSAgs em comparação com o estável, sem Abs contra KSAgs. SkP TxRs com rejeição mostrou aumento das frequências de IFN-γ e IL-17 da KSAg com redução nas células secretantes IL-10.…”

“…SkP TxRs com rejeição mostrou aumento das frequências de IFN-γ e IL-17 da KSAg com redução nas células secretantes IL-10. Tudo isso demonstra que o SkP TxRs com rejeição desenvolveu Abs para KSAgs e PSAgs, aumentando as células INF-γ específicas do rim ou do pâncreas, e células de segregação IL-17 com IL-10 reduzidas, sugerindo perda de tolerância periférica para SAgs(Gunasekaran, 2017).Na avaliação do aumento da produção de C-peptídeos, avaliou-se a rejeição ou a falha do pâncreas transplantado. Para tal, investigaram-se pacientes com 5 anos de acompanhamento pós-transplante de TSPR e com níveis de C-peptídeos coletados em consultas.…”