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Published on: September 12, 2019
89Zr-pro-MMP-9 F(ab')2 detects colitis induced intestinal and kidney fibrosis
Nicole Dmochowska1, William Tieu2, Marianne D Keller1,3
1Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia.
Abstract:
Intestinal fibrosis is a common complication of inflammatory bowel disease but remains difficult to detect. Matrix metalloproteases (MMPs) have key roles in fibrosis and are therefore potential targets for fibrosis detection. We determined whether immunoPET of F(ab')2 antibody fragments targeting MMPs detects colitis induced colonic fibrosis. Mice were administered 2% dextran sulfate sodium treated water for 1 cycle (inflamed) or 3 cycles (fibrotic), or were untreated (control). Colonic and kidney collagen, innate cytokine, MMPs and fecal MPO concentrations were analyzed by multiplex/ELISA. α-pro-MMP-9 F(ab')2 fragments were engineered and conjugated to 89Zr for PET imaging, ex-vivo Cherenkov analysis and bio-distribution. Colonic innate cytokine concentrations and fecal myeloperoxidase were increased in inflamed mice but not fibrotic mice, while collagen concentrations were increased in fibrotic mice. MMPs were increased in inflamed mice, but only pro-MMP-9 remained increased in fibrotic mice. 89Zr-pro-MMP-9 F(ab')2 uptake was increased in the intestine but also in the kidney of fibrotic mice, where collagen and pro-MMP-9 concentrations were increased. 89Zr-pro-MMP-9 F(ab')2 detects colitis induced intestinal fibrosis and associated kidney fibrosis.
Insights
ImmunoPET imaging using 89Zr-labeled antibody fragments targeting pro-matrix metalloproteinase-9 (MMP-9) effectively detects intestinal fibrosis in colitis models. This approach also identifies associated kidney fibrosis, offering a novel diagnostic tool.
Area of Science:
- Biomedical Imaging
- Molecular Imaging
- Immunology
Background:
- Intestinal fibrosis, a complication of inflammatory bowel disease, is challenging to detect.
- Matrix metalloproteinases (MMPs) play crucial roles in fibrosis development and are potential diagnostic targets.
Purpose of the Study:
- To evaluate the efficacy of immunoPET imaging with 89Zr-labeled F(ab')2 antibody fragments targeting MMPs for detecting colitis-induced intestinal fibrosis.
- To assess the correlation between imaging findings and established biomarkers of fibrosis and inflammation.
Main Methods:
- Mice were subjected to dextran sulfate sodium (DSS) treatment to induce colitis with varying degrees of fibrosis.
- ImmunoPET imaging was performed using 89Zr-conjugated α-pro-MMP-9 F(ab')2 fragments.
- Colonic and kidney tissues were analyzed for collagen, cytokine, MMP, and myeloperoxidase (MPO) levels.
Main Results:
- Fibrotic mice showed increased collagen in the colon and kidney, with elevated pro-MMP-9 levels.
- 89Zr-pro-MMP-9 F(ab')2 uptake was significantly increased in the fibrotic intestines and kidneys.
- Imaging results correlated with increased collagen and pro-MMP-9 concentrations in fibrotic tissues.
Conclusions:
- 89Zr-pro-MMP-9 F(ab')2 immunoPET is a viable method for detecting colitis-induced intestinal fibrosis.
- The imaging technique also successfully identified associated kidney fibrosis, highlighting its potential for comprehensive disease assessment.
