Dataset Information

Immuno-PET of Innate Immune Markers CD11b and IL-1? Detects Inflammation in Murine Colitis.

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD are reliant on endoscopy, which is invasive and does not provide information on specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis; however, a direct comparison of antibodies targeted to innate immune mediators and cells has not been done. We aimed to compare immuno-PET of antibodies to IL-1? and CD11b against standard ¹⁸F-FDG and MRI approaches to detect colonic inflammation. Methods: Colonic concentrations of IL-1? and myeloperoxidase were determined by ELISA, and colonic infiltration by CD11b-positive CD3-negative innate immune cells was determined by flow cytometry and compared between healthy and dextran sodium sulphate-treated colitic mice. PET of ⁸⁹Zr-l?-IL-1?, ⁸⁹Zr-?-CD11b, and ¹⁸F-FDG was compared by volume-of-interest analysis and with MRI by region-of-interest analysis. Imaging results were confirmed by ex vivo biodistribution analysis. Results: Colonic inflammation was associated with impaired colonic epithelial barrier permeability, increased colonic IL-1? and myeloperoxidase concentrations, and increased CD11b-positive CD3-negative innate immune cell infiltration into the colon. ⁸⁹Zr-?-IL-1? and ⁸⁹Zr-?-CD11b immuno-PET detected colonic inflammation, as did ¹⁸F-FDG, and all PET tracers were more sensitive than MRI. Although ¹⁸F-FDG volumes of interest correlated with colitis severity and a strong trend was observed with ⁸⁹Zr-?-IL-1?, no correlation was observed for ⁸⁹Zr-?-CD11b or MRI. ⁸⁹Zr-?-IL-1? was distributed mainly to the gastrointestinal tract, whereas ⁸⁹Zr-?-CD11b was distributed to more tissue types. Conclusion: Immuno-PET using antibodies directed to innate immune markers detected colonic inflammation, with ⁸⁹Zr-?-IL-1? providing a more tissue-specific signal than ⁸⁹Zr-?-CD11b. Development of these technologies for human subjects will potentially provide a less invasive approach than endoscopy for diagnosing and monitoring IBD.

SUBMITTER: Dmochowska N

PROVIDER: S-EPMC6581233 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Immuno-PET of Innate Immune Markers CD11b and IL-1β Detects Inflammation in Murine Colitis.

Dmochowska Nicole N Tieu William W Keller Marianne D MD Wardill Hannah R HR Mavrangelos Chris C Campaniello Melissa A MA Takhar Prab P Hughes Patrick A PA

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20181109 6

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD are reliant on endoscopy, which is invasive and does not provide information on specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis; however, a direct comparison of antibodies targeted to innate immune med ...[more]

PMID: 30413657

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Project description:Inflammatory bowel diseases (IBDs) in humans are characterized in part by aberrant CD4-positive (CD4+) T-cell responses. Currently, identification of foci of inflammation within the gut requires invasive procedures such as colonoscopy and biopsy. Molecular imaging with antibody fragment probes could be used to noninvasively monitor cell subsets causing intestinal inflammation. Here, GK1.5 cys-diabody (cDb), an antimouse CD4 antibody fragment derived from the GK1.5 hybridoma, was used as a PET probe for CD4+ T cells in the dextran sulfate sodium (DSS) mouse model of IBD. Methods: The DSS mouse model of IBD was validated by assessing changes in CD4+ T cells in the spleen and mesenteric lymph nodes (MLNs) using flow cytometry. Furthermore, CD4+ T cell infiltration in the colons of colitic mice was evaluated using immunohistochemistry. 89Zr-labeled GK1.5 cDb was used to image distribution of CD4+ T cells in the abdominal region and lymphoid organs of mice with DSS-induced colitis. Region-of-interest analysis was performed on specific regions of the gut to quantify probe uptake. Colons, ceca, and MLNs were removed and imaged ex vivo by PET. Imaging results were confirmed by ex vivo biodistribution analysis. Results: An increased number of CD4+ T cells in the colons of colitic mice was confirmed by anti-CD4 immunohistochemistry. Increased uptake of 89Zr-maleimide-deferoxamine (malDFO)-GK1.5 cDb in the distal colon of colitic mice was visible in vivo in PET scans, and region-of-interest analysis of the distal colon confirmed increased activity in DSS mice. MLNs from colitic mice were enlarged and visible in PET images. Ex vivo scans and biodistribution confirmed higher uptake in DSS-treated colons (DSS, 1.8 ± 0.40; control, 0.45 ± 0.12 percentage injected dose [%ID] per organ, respectively), ceca (DSS, 1.1 ± 0.38; control, 0.35 ± 0.09 %ID per organ), and MLNs (DSS, 1.1 ± 0.58; control, 0.37 ± 0.25 %ID per organ). Conclusion:89Zr-malDFO-GK1.5 cDb detected CD4+ T cells in the colons, ceca, and MLNs of colitic mice and may prove useful for further investigations of CD4+ T cells in preclinical models of IBD, with potential to guide development of antibody-based imaging in human IBD.

Dataset Information

Immuno-PET of Innate Immune Markers CD11b and IL-1? Detects Inflammation in Murine Colitis.

Publications

Immuno-PET of Innate Immune Markers CD11b and IL-1β Detects Inflammation in Murine Colitis.

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