Korean J Radiol.  2009 Oct;10(5):472-480. 10.3348/kjr.2009.10.5.472.

Molecular MR Imaging for Visualizing ICAM-1 Expression in the Inflamed Synovium of Collagen-Induced Arthritic Mice

• Lee SI
• Lee SY
• Yoon KH
• Choi KS
• Jang KY
• Yoo WH
• Kim SH
• Choi TH
• Park JG

• KMID: 1093962
• DOI: http://doi.org/10.3348/kjr.2009.10.5.472

Abstract

OBJECTIVE
To determine the utility of intercellular adhesion molecule (ICAM)-1 antibody-conjugated gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA-anti-ICAM-1) as a targeted contrast agent for the molecular magnetic resonance imaging (MRI) in collagen-induced arthritis (CIA). MATERIALS AND METHODS: Three groups of mice were used: non-arthritic normal, CIA mice in both the early inflammatory and chronic destructive phases. The MR images of knee joints were obtained before and after injection of Gd-DTPA-anti-ICAM-1, Gd-DTPA, and Gd-DTPA-Immunoglobulin G (Ig G) and were analyzed quantitatively. The patterns of enhancement on the MR images were compared with the histological and immunohistochemical ICAM-1 staining. RESULTS: The images obtained after injection of Gd-DTPA-anti-ICAM-1 displayed gradually increasing signal enhancement from the moment following injection (mean +/- standard deviation [SD]: 424.3 +/- 35.2, n = 3) to 24 hours (532 +/- 11.3), rather than on pre-enhanced images (293 +/- 37.6) in the early inflammatory phase of CIA mice. However, signal enhancement by Gd-DTPA and Gd-DTPA-IgG disappeared after 80 minutes and 24 hours, respectively. In addition, no significant enhancement was seen in the chronic destructive phase of CIA mice, even though they also showed inflammatory changes on T2-weighted MR images. ICAM-1 expression was demonstrated in the endothelium and proliferating synovium of the early inflammatory phase of CIA mice, but not in the chronic destructive phase. CONCLUSION: Molecular MRI with Gd-DTPA-anti-ICAM-1 displays specific images targeted to ICAM-1 that is expressed in the inflamed synovium of CIA. This novel tool may be useful for the early diagnosis and differentiation of the various stages of rheumatoid arthritis.

Keyword

Intercellular adhesion molecules; Gadolinium; Magnetic resonance (MR); Rheumatoid arthritis

MeSH Terms

Animals
Arthritis, Experimental/*metabolism
Collagen
Contrast Media
Disease Models, Animal
Gadolinium DTPA/diagnostic use
Intercellular Adhesion Molecule-1/*metabolism
Knee Joint/*metabolism/radiography
Magnetic Resonance Imaging/*methods
Male
Mice
Synovial Membrane/*metabolism/radiography

Figure

• 

  Fig. 1 MR images of knee joints in early inflammatory phase of collagen-induced arthritis mice. A. Gd-DPTA-injected; B. Gd-DPTA-anti-ICAM-1-injected; and C. Gd-DPTA-IgG-injected mice. In first column (far left), T2-weighted fat-suppressed MR images of arthritic knees of collagen-induced arthritis mice demonstrate thickened synovium and joint effusion as area of hyper-intense signal. Second column shows pre-contrast images; following columns (left to right) show dynamic T1-weighted MR images acquired immediately, 10 minutes, 30 minutes, 80 minutes, 2 hours, and 24 hours after injection of contrast agents. Quick T1 enhancement with Gd-DTPA was demonstrated immediately after injection and disappears after 80 minutes (A). MR images with Gd-DTPA-anti-ICAM-1 display gradually increasing signal enhancement in arthritic knee for 24 hours after injection of this targeted contrast agent (B). Signal enhancement with Gd-DTPA-IgG is observed for only 30-80 minutes after injection and disappears after 24 hours (C).

• 

  Fig. 2 Comparisons of mean enhancement curves in early inflammatory phase of collagen-induced arthritis mice injected with Gd-DTPA (n = 3), Gd-DTPA-anti-ICAM-1 (n = 3), or Gd-DTPA-IgG (n = 3) at different times. Quick T1 enhancement (mean ± SD: 393.0 ± 49.1, n = 3) was demonstrated immediately after injecting Gd-DTPA (100 nmoles of Gd/gm of body weight) compared to pre-enhanced images (212.3 ± 35.4) and decreased at 80 minutes (254.7 ± 20.2). Gd-DTPA-anti-ICAM-1 enhanced images display gradually increasing signal enhancement from immediately (mean ± SD: 424.3 ± 35.2, n = 3) to 24 hours (532.0 ± 11.3) compared to pre-enhanced images (293 ± 37.6). MR images with Gd-DTPA-IgG show signal enhancement only for 30-60 minutes after injection and this T1 enhancement disappears within 24 hours.

• 

  Fig. 3 MR images with Gd-DTPA-anti-ICAM-1 of knee joint of mouse in chronic destructive phase of collagen-induced arthritis. A. T2-weighted fat-suppressed MR image demonstrates synovitis and destruction of knee joints (arrows). B. Image obtained before injection. C-H. T1-weighted serial MR images obtained immediately, 10 minutes, 30 minutes, 1 hour, 2 hours, and 24 hours after Gd-DTPA-anti-ICAM-1 injection. Very little to no signal enhancement is observed in arthritic knee joints for up to 24 hours after injection of targeted contrast agent.

• 

  Fig. 4 Comparison of mean enhancement curves between early (n = 3) and chronic (n = 3) phases of collagen-induced arthritis in mice injected with Gd-DTPA-anti-ICAM-1 at different times. MR images obtained from mice in chronic destructive phase of collagen-induced arthritis, after injection of Gd-DTPA-anti-ICAM-1, show no significant signal enhancement for up to 24 hours. CIA = collagen-induced arthritis

• 

  Fig. 5 MR images, plain films, as well as histopathological and immunohistochemical findings in A. non-arthritic normal mouse; B. early inflammatory phase; and C. chronic destructive phase of collagen-induced arthritis mice. In first column, T2-weighted fat-suppressed MR images show hyper-intense signals in arthritic joints in early inflammatory (B) and chronic destructive phases (C) of collagen-induced arthritis. In second column, ICAM-1-targeted T1-weighted MR images significant signal enhancement was demonstrated uniquely in mouse in early inflammatory phase of collagen-induced arthritis (B). In third column, only mouse in chronic destructive phase of collagen-induced arthritis showed bone erosion (arrows) under plain radiographs (C). Hematoxylin & Eosin staining (fourth column) shows synovial hyperplasia (asterisks) in early inflammatory phase of collagen-induced arthritis (B) as well as marked pannus invasion and bone destruction (arrowheads) in chronic destructive phase of collagen-induced arthritis (C). In last column, dense ICAM-1 expression is shown only in endothelium of proliferating synovium of mouse in early inflammatory phase of collagen-induced arthritis (B).

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