Abstract: FR-OR082

Notch Receptor Expression Is Significantly Increased during Human Kidney Transplant Rejection

Session Information

Category: Transplantation

  • 1702 Transplantation: Clinical and Translational

Authors

  • Bowes, Amy, Royal Free London NHS Foundation Trust , London, United Kingdom
  • Morris, Kirsten, Royal Free London NHS Foundation Trust , London, United Kingdom
  • Murakami, Naoka, Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States
  • Bass, Paul, UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom
  • Salama, Alan D., UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom
  • Stauss, Hans J, UCL, London, United Kingdom
  • Riella, Leonardo V., Brigham and Women's Hospital, Harvard Medical School, Brookline, Massachusetts, United States
  • Magee, Ciara N., UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom
Background

Despite significant advances in transplantation, our ability to appropriately modify the immune response therein remains limited. Development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize immunosuppression. Notch receptor signaling is crucial to cell development and plays a key role in T cell activation and differentiation, though limited data exist on its importance in immune regulation. In this study, we investigated the pattern of Notch receptor expression in human renal transplantation.

Methods

Transplant kidney biopsy samples obtained from patients enrolled in an immune monitoring study in our institution were evaluated. All patients had a routine time zero biopsy; a subset of patients underwent further biopsy post-transplant due to episodes of graft dysfunction, and were classified as acute rejection (n=12), or non-rejection (n=15). Immunohistochemical analysis was performed to identify intact and activated (cleaved) Notch receptor expression (measured as % threshold area using ImageJ) on paraffin-embedded sections. Cellular samples were collected from another cohort of renal transplant patients during times of clinical quiescence or acute rejection and analyzed for T cell subset expression of Notch using flow cytometry.

Results

Renal expression of cleaved Notch1, cleaved and intact Notch2 was significantly increased in patients with acute rejection when compared to their baseline biopsies and post-transplant patients without rejection (p<0.0001, p<0.0001 & p<0.0001, respectively). Next, we investigated the expression of Notch1 in T conventional cells (Tconv; CD4+Foxp3-) and Tregs (CD4+Foxp3+) in transplant recipients. During clinical quiescence, a significantly higher proportion of Tregs expressed Notch1 compared to Tconv cells. However, there was a 100-fold increase in the proportion of Tconv expressing Notch1 during a rejection episode, with a slight reduction in the proportion of Tregs expressing Notch1.

Conclusion

We found that there is significant upregulation of both celluar and tissue Notch receptor expression during immune activation. Given the importance of Notch signaling in T cell activation, treatment with Notch inhibition may provide a novel means of attenuating cellular responses in transplantation.

Funding

  • Other NIH Support