Transcriptome Profiling Of Renal Transplant Biopsies With Acute Cellular Rejection From Patients On Calcineurin Inhibitor-based Or Cni-avoidance Immunosuppression
1Department of Pathology, University of California, San Francisco, San Francisco, CA, 2Departments of Medicine and Surgery, University of California, San Francisco, San Francisco, CA
Meeting: 2019 American Transplant Congress
Abstract number: A131
Keywords: Calcineurin, Gene expression, Kidney, Rejection
Session Information
Session Name: Poster Session A: Biomarkers, Immune Monitoring and Outcomes
Session Type: Poster Session
Date: Saturday, June 1, 2019
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall C & D
*Purpose: Despite their suboptimal toxicity profile, calcineurin-inhibitors (CNIs) remain the cornerstone of renal transplant immunosuppression. Previous efforts to completely eliminate CNIs failed, because CNI-avoidance protocols were associated with a higher frequency of acute cellular rejection (ACR), the causes of which are not well understood. Here, we studied the transcriptome profiles of biopsy samples with ACR from patients on CNI-based or CNI-avoidance protocols.
*Methods: 27 patients showing ACR were enrolled, 18 of which were treated with a CNI-based regimen, and 9 with the combination of mycophenolate-mofetil and steroids (Vincenti F. Transplantation, 2001). Gene expression analysis (GEA) and CD45 immunohistochemistry (IHC) were performed on sections from formalin-fixed paraffin-embedded tissues. For GEA, NanoString nCounter platform was used with a customized panel of 756 genes. CD45 IHC was followed by whole-slide digital image analysis to quantify the inflammatory cell count/mm2 tissue (ICC).
*Results: Frequency of ACR grades and cortical ICC was comparable between the treatment groups (1883 cell/ sqmm, in the CNI-treated group, vs. 1419 cell/sqmm, in samples from patients on a CNI-avoidance regimen, p = 0.493). ACR patients on mycophenolate-mofetil and steroids were characterized by a significant downregulation of a total of 115 interferon-, antigen processing-, and presentation-related genes relative to ACR patients on CNI-based regimen (Table 1).
| Log2 fold change | Lower confidence limit (log2) | Upper confidence limit (log2) | BY.p.value | |
| STAT1 | -1.13 | -1.69 | -0.575 | 0.00803 |
| STAT2 | -1.57 | -1.92 | -1.21 | 0.000000126 |
| HLA-DPB1 | -1.25 | -1.75 | -0.746 | 0.000865 |
| HLA-DRA | -1.23 | -1.76 | -0.706 | 0.00182 |
| CTSS | -1.16 | -1.73 | -0.584 | 0.00831 |
In contrast, members of pattern recognition receptor cascade along with myeloid chemotaxis facilitator CXCR2, and genes of the IL1 pathway were upregulated in the CNI-avoidance group (Table 2).
*Conclusions: Despite the comparable inflammatory load and ACR grades, there were significant differences in the intragraft transcriptomic profile between the two treatment groups. The higher level of involvement of the innate immunity in patients with CNI-avoidance immunosuppressive regimen points toward a possible role for CNIs in the suppression of innate immunity.
To cite this abstract in AMA style:
Dobi D, Vincenti F, Laszik ZG. Transcriptome Profiling Of Renal Transplant Biopsies With Acute Cellular Rejection From Patients On Calcineurin Inhibitor-based Or Cni-avoidance Immunosuppression [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/transcriptome-profiling-of-renal-transplant-biopsies-with-acute-cellular-rejection-from-patients-on-calcineurin-inhibitor-based-or-cni-avoidance-immunosuppression/. Accessed November 22, 2024.« Back to 2019 American Transplant Congress