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Resolution of cutaneous inflammation after local elimination of macrophages

Abstract

We constructed an immunotoxin, composed of an antibody directed against the high-affinity IgG receptor CD64 and Ricin-A, with the aim of resolving chronic inflammation through elimination of activated macrophages. In vitro, this immunotoxin proved very efficient in inducing apoptosis in activated macrophages, leaving resting and low CD64-expressing macrophages unaffected. We examined the activity of our immunotoxin in a sodium lauryl sulfate (SLS)-induced cutaneous inflammation model, using transgenic mice expressing human CD64. Upon intradermal injection of the immunotoxin (IT), cutaneous inflammation resolved in 24 h. This was demonstrated histologically by clearance of all CD64-expressing macrophages, followed by clearance of other inflammatory cells. Clinical parameters associated with inflammation, such as local skin temperature and vasodilation, also decreased. 

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Figure 1: U937 cells were cultured either with (black bars) or without (gray bars) IFNγ in the presence of varying concentrations of H22-R (A) or 197-R (B).
Figure 2: U937 cells undergo apoptosis after incubation with H22-R.
Figure 3: Effect of a single intradermal injection of IT on inflammatory cells in skin.
Figure 4: Microphotographs of skin sections of hFcγRI-transgenic mice showing the effect of intradermal H22-R injection.
Figure 5
Figure 6: Photograph of section of skin after intravenous injection of Evans blue.

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Acknowledgements

The authors wish to thank Drs C.A.F.M. Bruijnzeel-Koomen and K.D. Cooper for helpful discussion, Dr C. Somasundaram for skillful preparation of the immunotoxins, and Tom O'Toole for proofreading the manuscript.

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Correspondence to Theo Thepen.

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Thepen, T., van Vuuren, A., Kiekens, R. et al. Resolution of cutaneous inflammation after local elimination of macrophages . Nat Biotechnol 18, 48–51 (2000). https://doi.org/10.1038/71908

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