TNF-α Blockade Mitigates Immune Checkpoint–Related Nephritis in a Humanized Mouse Model

Victor D. Cuenca Narvaez; Coraima Nava Chavez; Omar Al Refai; Johanna E. J. Jacobs; Luis E. Gutierrez; Song Zhang; Xiaoyan Li; Jacob B. Hirdler; Michael F. Romero; Joerg Herrmann; Xiaogang Li; Haidong Dong; Alfonso Eirin; Sandra M. Herrmann

doi:10.1172/jci.insight.199694

TNF-α Blockade Mitigates Immune Checkpoint–Related Nephritis in a Humanized Mouse Model

Victor D. Cuenca Narvaez,¹ Coraima Nava Chavez,¹ Omar Al Refai,¹ Johanna E. J. Jacobs,² Luis E. Gutierrez,¹ Song Zhang,² Xiaoyan Li,¹ Jacob B. Hirdler,³ Michael F. Romero,¹ Joerg Herrmann,² Xiaogang Li,¹ Haidong Dong,³ Alfonso Eirin,¹ and Sandra M. Herrmann¹

Published March 5, 2026 - More info

View PDF

Abstract

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with pro-inflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into four experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA sequencing. Histology revealed increased renal infiltration of CD4⁺/CD8⁺ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA sequencing revealed shifts in immune cell populations and genes of interest including: Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and pro-inflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.

TNF-α Blockade Mitigates Immune Checkpoint–Related Nephritis in a Humanized Mouse Model

Victor D. Cuenca Narvaez,¹ Coraima Nava Chavez,¹ Omar Al Refai,¹ Johanna E. J. Jacobs,² Luis E. Gutierrez,¹ Song Zhang,² Xiaoyan Li,¹ Jacob B. Hirdler,³ Michael F. Romero,¹ Joerg Herrmann,² Xiaogang Li,¹ Haidong Dong,³ Alfonso Eirin,¹ and Sandra M. Herrmann¹

Article tools

Metrics

Go to

TNF-α Blockade Mitigates Immune Checkpoint–Related Nephritis in a Humanized Mouse Model

Victor D. Cuenca Narvaez,1 Coraima Nava Chavez,1 Omar Al Refai,1 Johanna E. J. Jacobs,2 Luis E. Gutierrez,1 Song Zhang,2 Xiaoyan Li,1 Jacob B. Hirdler,3 Michael F. Romero,1 Joerg Herrmann,2 Xiaogang Li,1 Haidong Dong,3 Alfonso Eirin,1 and Sandra M. Herrmann1

Article tools

Metrics

Go to

Sign up for email alerts

Victor D. Cuenca Narvaez,¹ Coraima Nava Chavez,¹ Omar Al Refai,¹ Johanna E. J. Jacobs,² Luis E. Gutierrez,¹ Song Zhang,² Xiaoyan Li,¹ Jacob B. Hirdler,³ Michael F. Romero,¹ Joerg Herrmann,² Xiaogang Li,¹ Haidong Dong,³ Alfonso Eirin,¹ and Sandra M. Herrmann¹