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Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients.

ABSTRACT: Background:Belatacept-based therapy in kidney transplant recipient has been shown to increase long-term renal allograft and patient survival compared with calcineurin inhibitor-based therapy, however, with an increased risk of acute T cell-mediated rejection (aTCMR). An improved understanding of costimulation blockade-resistant rejections could lead to a more personalized approach to belatacept therapy. Here, immunomic profiles of aTCMR biopsies of patients treated with either tacrolimus or belatacept were compared. Methods:Formalin-fixed paraffin-embedded renal transplant biopsies were used for immunohistochemistry and gene expression analysis using the innovative NanoString technique. To validate NanoString, transcriptomic profiles of patients with and without biopsy-proven aTCMR were compared. Biopsies from 31 patients were studied: 14 tacrolimus-treated patients with aTCMR, 11 belatacept-treated patients with aTCMR, and 6 controls without rejection. Results:A distinct pattern was seen in biopsies with aTCMR compared to negative controls: 78 genes had a higher expression in the aTCMR group (false discovery rate P value <.05 to 1.42e-05). The most significant were T cell-associated genes (CD3, CD8, and CD4; P < 1.98e-04), ?-interferon-inducible genes (CCL5, CXCL9, CXCL11, CXCL10, TBX21; P < 1.33e-04) plus effector genes (GNLY, GZMB, ITGAX; P < 2.82e-03). Immunophenotypical analysis of the classic immune markers of the innate and adaptive immune system was comparable between patients treated with either tacrolimus or belatacept. In addition, the transcriptome of both groups was not significantly different. Conclusions:In this small pilot study, no difference was found in immunomics of aTCMR biopsies of tacrolimus- and belatacept-treated patients. This suggests that clinically diagnosed aTCMR reflects a final common pathway of allorecognition which is unaffected by the type of immunosuppressive therapy.

SUBMITTER: van der Zwan M

PROVIDER: S-EPMC6324913 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients.

van der Zwan Marieke M Baan Carla C CC Colvin Robert B RB Smith Rex N RN White Rebecca A RA Ndishabandi Dorothy D Nigg Alex L AL van den Bosch Thierry P P TPP de Graav Gretchen N GN Clahsen-van Groningen Marian C MC Hesselink Dennis A DA

Transplantation direct 20181220 1

<h4>Background</h4>Belatacept-based therapy in kidney transplant recipient has been shown to increase long-term renal allograft and patient survival compared with calcineurin inhibitor-based therapy, however, with an increased risk of acute T cell-mediated rejection (aTCMR). An improved understanding of costimulation blockade-resistant rejections could lead to a more personalized approach to belatacept therapy. Here, immunomic profiles of aTCMR biopsies of patients treated with either tacrolimus ...[more]

PMID: 30656216

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Project description:The data set contains 67 array (lymphochip cDNA array), published in N Engl J Med 2003 Jul 10;349(2):125-38. PMID: 12853585. TITLE: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. BACKGROUND: The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment. METHODS: We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles. : We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001). CONCLUSIONS: Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: normal vs disease Keywords: disease_state_design Using regression correlation

Dataset Information

Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients.

Publications

Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients.

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