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Noninvasive imaging of immune responses

Rashidian, Mohammad, Keliher, Edmund J., Bilate, Angelina M., Duarte, Joao N., Wojtkiewicz, Gregory R., Jacobsen, Johanne Tracey, Cragnolini, Juanjo, Swee, Lee Kim, Victora, Gabriel D., Weissleder, Ralph, Ploegh, Hidde L.
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.19 pp. 6146-6151
image analysis, immune response, monitoring, neoplasms, patients, positron-emission tomography, therapeutics
At their margins, tumors often contain neutrophils, dendritic cells, and activated macrophages, which express class II MHC and CD11b products. The interplay between stromal cells, tumor cells, and migratory cells such as lymphocytes creates opportunities for noninvasive imaging of immune responses. We developed alpaca-derived antibody fragments specific for mouse class II MHC and CD11b products, expressed on the surface of a variety of myeloid cells. We validated these reagents by flow cytometry and two-photon microscopy to obtain images at cellular resolution. To enable noninvasive imaging of the targeted cell populations, we developed a method to site-specifically label VHHs [the variable domain (V H) of a camelid heavy-chain only antibody] with ¹⁸F or ⁶⁴Cu. Radiolabeled VHHs rapidly cleared the circulation ( t ₁/₂ ≈ 20 min) and clearly visualized lymphoid organs. We used VHHs to explore the possibility of imaging inflammation in both xenogeneic and syngeneic tumor models, which resulted in detection of tumors with remarkable specificity. We also imaged the infiltration of myeloid cells upon injection of complete Freund’s adjuvant. Both anti-class II MHC and anti-CD11b VHHs detected inflammation with excellent specificity. Given the ease of manufacture and labeling of VHHs, we believe that this method could transform the manner in which antitumor responses and/or infectious events may be tracked.