28 September 2007. Researchers led by Robin Choudhury at Oxford University, England, have developed a new magnetic resonance imaging method that could help with the diagnosis and management of multiple sclerosis. The technique uses antibodies tagged with microparticles of iron oxide (MPIO) to detect expression of VCAM (endothelial vascular cell adhesion molecule) in blood vessels of the mouse brain. VCAM, a mediator of leukocyte recruitment, is not constitutively expressed in cerebral endothelium but is an excellent marker for acute brain inflammation. The new technique, described in the September 23 Nature Medicine online, could be adapted to monitor other endovascular molecules implicated in different pathologies, suggest the authors.
One of the main advantages of the new technique is that it can detect inflammation long before other multiple sclerosis (MS) pathologies are apparent. Current diagnostic criteria for multiple sclerosis include both clinical assessment and magnetic resonance imaging (MRI) of neural lesions, for example. However, both are limited because they only detect advanced pathology and give little indication of disease progression. The new imaging technique aims to overcome these problems.
First author Martina McAteer and colleagues tested the technique in mice. They chose VCAM as a target because this cell surface protein and its ligand, α4β1 integrin, are key mediators of leukocyte recruitment. Blocking the VCAM/α4β1 integrin interaction also prevents inflammation and paralysis associated with experimental autoimmune encephalitis, a widely used rodent model of MS. After testing the specificity of the VCAM-MPIO antibodies in vitro using mouse endothelial cells, the researchers administered them to mice that had received a stereotactic injection of the proinflammatory cytokine interleukin-1β (IL-1β) to one side of the brain. Magnetic resonance imaging of the treated animals showed marked signals delineating blood vessels on the IL-1β side of the brain. The contralateral side showed minimal signal (see figure below).
Magnetic VCAM Antibodies Image Multiple Sclerosis
A composite of magnetic resonance images shows that interleukin 1β given to one brain hemisphere stimulated activation of the inflammatory marker VCAM on that side, but not on the contralateral side. The inflammation is revealed by antibodies tagged with microparticles of iron oxide. Image credit: Robin Choudhury
This MPIO approach has much appeal, suggest the authors. In addition to improving diagnosis, VCAM-MPIO antibodies could be used to identify patients who might respond to natalizumab, a humanized monoclonal antibody to α4 integrins that is being used to treat MS. “More broadly, by modifying the ligand, MPIO constructs could readily be adapted to image other endovascular targets that are differentially expressed in a broad range of pathologies,” write the authors. The technique is not ready for prime time, however. The current generation of MPIOs is not biodegradable and so cannot be used in humans, though the authors write that synthesizing biodegradable versions should be feasible. For more on that, and on other potential uses, see Q&A below with Robin Choudhury.—Tom Fagan.
McAteer MA, Sibson NR, von zur Muhlen C, Schneider JE, Lowe AS, Warrick N, Channon KM, Anthony DC, Choudhury RP. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nature Medicine. 2007 Sep 23, online. Abstract
Q&A with Robin Choudhury. Questions by Tom Fagan and Gabrielle Strobel.
Q: The MPIO you used are non-biodegradable and so cannot be used in humans. You write about the possibility of synthesizing biodegradable particles. Is that technically challenging? Would the particles be any less suitable?
A: That's right. We used commercial particles that are more usually used for cell sorting. Companies already make clinical-grade particles that can be injected into humans and “bio-dispersed” (albeit smaller than those used in this study). We don't see any theoretical obstacle to synthesizing clinically usable MPIOs, but clearly this requires considerable further study.
Q: Are you planning on eventually taking this into humans? How feasible and how far off?
A: That is the goal. We purposely used an iron-based contrast and at a dose close to that approved by regulatory authorities for other iron-based contrast. We need to explore a number of issues relating to how beads of this size are handled, and those studies are underway.
Q: What other targets are you thinking of applying this technique to?
A: We looked at both P-selectin and glycoprotein IIb/IIIa on activated platelets. Both are attractive endovascular targets.
Q: Inflammatory responses are part of AD pathology; do you think VCAM-1 plays any role in AD?
A: VCAM is involved in the recruitment of mononuclear leucocytes and therefore tends to be upregulated in inflammatory conditions, e.g., atherosclerosis, arthritis, and some neurological conditions such as MS. I am not aware of any VCAM upregulation on AD.
Q: Would it make sense to test these VCAM-MPIO antibodies in mouse models of AD or CAA?
A: Only if VCAM is known/shown to be to be upregulated on the vascular endothelium in these models.
Q: Do you think a blood-brain barrier permeable version of these MPIOs would be useful?
A: I do not. These particles are far too big to be desirable in the brain! There are smaller imaging particles, but as we discuss in the paper, these have inherently different handling and contrast properties and are less attractive for this application.
Q: Would introducing iron oxide into the brain pose a health risk?
A: Probably not in the doses we would propose and if the iron remained intravascular prior to disposal in the spleen. But this is not really known. There is a paper out this month looking at iron oxide microparticle accumulation in the brain in acute stroke in humans (Saleh et al., 2007).
Q: How does the technique compare to other imaging markers of inflammation, such as 11C-PK11195?
A: No data are available to answer this.
Q: How about other emerging techniques? Do you think magnetic antibodies will receive widespread use?
A: I hope so. I think their potential in research is huge. It is too early to know about the clinic....