Immuno-oncology

Oral

Acute Interstitial Nephritis Secondary to Programmed death-1 (pd-1) Blockade: role for pd-1 Ligands in Human T Cell-renal Microvascular Endothelial Interactions

Thursday, June 15
5:45 PM - 7:00 PM

Human renal microvascular endothelial cells (RMEC) express high levels of MHC class II proteins under non-pathologic conditions. Prior preliminary data indicated that isolated RMEC activate T cells in a class II peptide dependent manner leading to T cell proliferation and cytokine secretion. This effect was blocked by antibodies to CD40, CD58 and HLADR; and enhanced by antibodies to PDL1 (B7H1, CD274). We hypothesized that RMEC limit T cell activation to HLA class II presented peptides by the PD-1 pathway.

Stimulatory and inhibitory second signaling proteins on RMEC (CD34+, HLADR+, CD45-) and renal T cells (CD45+, CD3+) were assessed using flow cytometry. RMEC express CD58, CD275 (ICOS L), CD274 (PDL1), CD273 (PDL2), B7H3 and B7H4; they lack CD80 and CD86. Renal T cells express CD2, CD28, CD274 (PDL1) and CD279 (PD1). Secondary signal effects on T cell activation are being evaluated with cultured RMEC and anti-CD3 stimulation of T cells.

Four cases of acute kidney injury in patients receiving PD-1 blocking monoclonal antibodies for their cancers were identified. Biopsies revealed an intense non-eosinophilic interstitial nephritis in the area of the class II expressing RMEC. This suggests a role of PD-1 ligands in limiting T cell mediated renal inflammation.

Our interpretation of RMEC's ability to activate T cells, their high levels of PD-1 ligands and now the development of interstitial inflammation in patients receiving anti-PD1 monoclonal therapy is that RMEC are poised to present peptide as an immune surveillance system, with the PD1 pathway functioning to restrain T cell activation.

Kimberly Muczynski

University of Washington

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    Maria Elena Danoviz

    University of Washington

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      Bairbre McNicholas

      University of Washington

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        Mark Joseph Torres

        University of Washington

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          Jonas Kwiatkowski

          University of Washington

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            Susan Anderson

            University of Washington

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