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Abstract: FR-PO077

A Mechanism for Interstitial Nephritis Associated with “Checkpoint” Blockade: Unleashing Renal Microvascular Endothelial Cell (RMEC) Secondary Signals for T Cell Activation

Session Information

  • AKI Clinical: Predictors
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 003 AKI: Clinical and Translational


  • Muczynski, Kimberly A., University of Washington, Seattle, Washington, United States
  • McNicholas, Bairbre A., University of Washington, Seattle, Washington, United States
  • Anderson, Susan K., University of Washington, Seattle, Washington, United States
  • Danoviz, Maria E, University of Washington, Seattle, Washington, United States

T cell activation is a two-step process: 1) T cell receptor recognition of an antigenic peptide presented by a HLA molecule; and 2) engagement of activating secondary signal molecules. The second step is actually more complex because antigen presenting cells may have both stimulatory and inhibitory molecules for T cell activation. A new approach for treating metastatic cancer is to block inhibitory second signals such as the programmed death-1 (PD-1) pathway, allowing T cells greater activation and killing of a tumor. We and others have identified cases of interstitial nephritis in patients treated with the new “checkpoint” blockers (eg nivolumab, pembrolizumab).
Other work in the lab identified high levels of HLA class II molecules on RMEC of normal kidneys without inflammation. We have been puzzled by this due to the potential exposure of RMEC to circulating peptides; and we found that isolated RMEC activate T cells in a class II-peptide dependent manner. We hypothesize that RMEC express inhibitory second signals which limit their ability to activate T cells.


Ex-vivo renal T cells and RMEC from normal human kidneys were evaluated by flow cytometry for expression of inhibitory and stimulatory second signal molecules. An assay was developed using CD3-activated T cells with isolated RMEC to assess the role of second signal molecules.


RMEC express activating secondary signal molecules CD58 and CD275; and inhibitory molecules CD274 (PDL1), CD273 (PDL2), CD276 (B7-H3) and B7-H4. Intrarenal T cells in normal human kidney express CD28, CD2, CD274 (PDL1) and CD279 (PD1). Blockade of PD-1 or its ligands, or B7-H4 enhance T cell activation measured as cytokine release and expression of CD69. Blockade of CD58 or CD2 decreases T cell activation.


A unifying interpretation of results is that RMEC, while capable of activating T cells when the appropriate peptide is presented, limit the strength of the response by the PD-1 pathway. Blocking the PD-1 pathway with checkpoint agents unleashes RMEC’s stimulatory second signal molecules creating the potential for inflammation when there is an appropriate signal 1. We suggest interstitial nephritis develops when a RMEC-T cell signal 1 is engaged in the presence of checkpoint blockade.


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