Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability
Sam C. Nalle, … , Peter A. Savage, Jerrold R. Turner
Sam C. Nalle, … , Peter A. Savage, Jerrold R. Turner
Published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):902-914. https://doi.org/10.1172/JCI98554.
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Research Article Gastroenterology Oncology

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

Abstract

Graft-versus-host disease (GVHD) is a complication of hematopoietic stem cell transplantation (HSCT) that affects multiple organs. GVHD-associated intestinal damage can be separated into two distinct phases, initiation and propagation, which correspond to conditioning-induced damage and effector T cell activation and infiltration, respectively. Substantial evidence indicates that intestinal damage induced by pretransplant conditioning is a key driver of GVHD initiation. Here, we aimed to determine the impact of dysregulated intestinal permeability on the subsequent GVHD propagation phase. The initiation phase of GVHD was unchanged in mice lacking long MLCK (MLCK210), an established regulator of epithelial tight junction permeability. However, MLCK210-deficient mice were protected from sustained barrier loss and exhibited limited GVHD propagation, as indicated by reduced histopathology, fewer CD8+ effector T cells in the gut, and improved overall survival. Consistent with these findings, intestinal epithelial MLCK210 expression and enzymatic activity were similarly increased in human and mouse GVHD biopsies. Intestinal epithelial barrier loss mediated by MLCK210 is therefore a key driver of the GVHD propagation. These data suggest that inhibition of MLCK210-dependent barrier regulation may be an effective approach to limiting GVHD progression.

Authors

Sam C. Nalle, Li Zuo, Ma. Lora Drizella M. Ong, Gurminder Singh, Alicia M. Worthylake, Wangsun Choi, Mario Cabrero Manresa, Anna P. Southworth, Karen L. Edelblum, Gregory J. Baker, Nora E. Joseph, Peter A. Savage, Jerrold R. Turner

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Figure 4

GVHD severity is markedly reduced in MLCK–/– mice.

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GVHD severity is markedly reduced in MLCK–/– mice. B6 WT or MLCK–/– reci...
B6 WT or MLCK–/– recipients were lethally irradiated, followed by a syngeneic (B6) or allogeneic (129) BMT. (A) Relative weight and (B) disease activity scores (n = 8–12/group). *P < 0.05, 2-tailed t tests on d35 (129→WT vs. 129→MLCK–/–). (C) Serum TNF as determined by ELISA, 35 days after BMT. Each point represents an individual mouse. **P < 0.01, 2-tailed t test (129→WT vs. 129→MLCK–/–). (D) Survival (n = 6–8/group). **P < 0.01, Kaplan-Meier log-rank test (129→WT vs. 129→MLCK–/–). (E and F) Liver, skin, and jejunum were harvested 35 days after BMT and sections immunostained for CD8 (green) and E-cadherin (ECAD, red). (E) Representative images of biliary and squamous (skin) epithelium from WT (left panels) and MLCK–/– (right panels) mice are shown. Arrowheads denote infiltration by CD8+ cells. Scale bars: 20μm. (F) Representative images of jejunum from WT (left) and MLCK–/– (right) mice. Arrowheads denote direct contact of CD8+ cells with the epithelium. Scale bar: 50 μm. (G) Jejunum harvested 35 days after BMT was immunostained for CD3, CD4, Foxp3, and T-bet. Graphs show CD3+, CD4+Foxp3+, or CD4+T-bet+ T cells. Each point represents an individual mouse. **P < 0.01, 2-tailed t test.