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Trained immunity suppression determines kidney allograft survival

ABSTRACT: The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280787 | GEO | 2024/11/04

REPOSITORIES: GEO

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Project description:We study the global gene expression profiles of TGP patients with or without graft loss to determine if a clinical and/or gene expression profile can predict allograft survival. Transplant glomerulopathy (TGP) carries a poor prognosis and is associated with decreased allograft survival. In a large series of kidney transplant recipients, graft loss was observed in 38% of TGP patients at 5 years compared to 5% in patients without TGP. Among patients with TGP, predictors of poor outcome included C4d deposition in the peritubular capillaries, higher serum creatinine and proteinuria at diagnosis, the severity of interstitial fibrosis, and GBM duplication (higher Banff M-bM-^@M-^Xchronic glomerulopathy [cg]M-bM-^@M-^Y score), and the presence of DSA. However, the importance of microvascular inflammation determined by peritubular capillaritis (ptc) and glomerulitis (g) scores and the strength of DSA has not been explored thoroughly. We have recently reported the intragraft gene expression profiles of TGP patients, with or without DSA. However, the association between gene expression profiles of biopsies and the allograft survival has not been investigated. In this study, in addition to known clinical and demographic factors associated with poor outcomes in TGP, we specifically aimed to investigate if intragraft gene expression profiles by microarrays, microvascular inflammation scores, and the strength of DSA determined by mean fluorescence intensity (MFI) values could predict allograft loss in TGP patients. The study population was derived from renal allograft biopsies diagnosed with TGP at Montefiore Medical Center, Bronx, NY from January 2009 to December 2012. All biopsies were clinically indicated for elevated creatinine or proteinuria. A retrospective chart review was conducted to record clinical, demographic, immunological, and histopathological parameters and graft outcomes. Graft loss was defined as requiring dialysis and/or retransplantation during follow-up. Of the 525 patients who underwent clinically indicated transplant kidney biopsies, 52 patients (10%) had diagnosis of TGP. Median follow up time after the biopsy was 23 months (range, 1-46). Seventeen patients (32%) lost their allografts (defined by return to dialysis or re-transplantation) at a median time of 16 months (range, 1-44). A subgroup of patients who were enrolled in the IRB-approved M-bM-^@M-^\Immune Monitoring StudyM-bM-^@M-^] and had clinically indicated biopsy samples were included in the analysis. A total of 28 biopsy samples (8 graft loss and 20 functioning allograft) were used for gene expression profiling.

Project description:Background: Despite significant improvements in short-term kidney transplant survival, comparable increases in 5 and 10-year outcomes have not been achieved. Chronic allograft nephropathy (CAN) is a major cause of late graft loss. Toxic nephropathy and inadequate long-term immunosuppression are possible factors. We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure, and gene expression. Methods: Sixty-one kidney recipients received mycophenolate mofetil (MMF), and prednisone (P). Randomized patients received concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Findings: Comparing sirolimus/MMF/P to cyclosporine/MMF/P at two years, there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dl; p=0.008), significantly higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 cc/min; p=0.008), iothalamate GFR (60.6 vs. 49.2 cc/min; p= 0.018), and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p=0.013). Regression analysis of calculated GFR’s from 1 to 36 months yielded a positive slope for sirolimus of 3.36 ml/min/year, and a negative slope for cyclosporine of –1.58 ml/min/year (p=0.008). Gene expression profiles of kidney biopsies with higher Banff CAN scores confirmed significant up regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. Interpretation: At two years the sirolimus-treated patients have better renal transplant function, a diminished prevalence of CAN, and down regulated expression of genes responsible for the progression of CAN. All may provide for an alternative natural history with improved graft survival. Keywords = Cyclosporine Keywords = Sirolimus Keywords = Transplantation Keywords = DNA microarrays Keywords = calcineurin inhibitors Keywords: parallel sample. This dataset is part of the TransQST collection.

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Trained immunity suppression determines kidney allograft survival

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