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Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function
Epameinondas Gousopoulos, … , Lothar C. Dieterich, Michael Detmar
Epameinondas Gousopoulos, … , Lothar C. Dieterich, Michael Detmar
Published October 6, 2016
Citation Information: JCI Insight. 2016;1(16):e89081. https://doi.org/10.1172/jci.insight.89081.
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Research Article Dermatology Vascular biology

Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function

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Abstract

Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell–related networks, and indeed depletion of CD4+ cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema. Indeed, increased infiltration of Tregs was identified in mouse lymphedematous skin and in human lymphedema specimens. To investigate the role of Tregs during disease progression, loss-of-function and gain-of-function studies were performed. Depletion of Tregs in transgenic mice with Tregs expressing the primate diphtheria toxin receptor and green fluorescent protein (Foxp3-DTR-GFP) mice led to exacerbated edema, concomitant with increased infiltration of immune cells and a mixed TH1/TH2 cytokine profile. Conversely, expansion of Tregs using IL-2/anti–IL-2 mAb complexes significantly reduced lymphedema development. Therapeutic application of adoptively transferred Tregs upon lymphedema establishment reversed all of the major hallmarks of lymphedema, including edema, inflammation, and fibrosis, and also promoted lymphatic drainage function. Collectively, our results reveal that Treg application constitutes a potential new curative treatment modality for lymphedema.

Authors

Epameinondas Gousopoulos, Steven T. Proulx, Samia B. Bachmann, Jeannette Scholl, Dimitris Dionyssiou, Efterpi Demiri, Cornelia Halin, Lothar C. Dieterich, Michael Detmar

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Figure 1

Lymphedema development is characterized by inflammation.

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Lymphedema development is characterized by inflammation.
(A) Schematic r...
(A) Schematic representation of the number of genes uniquely or commonly upregulated 2 and 6 weeks after surgery. (B) Schematic representation of the number of genes uniquely or commonly downregulated 2 and 6 weeks after surgery. (C) List of the 10 most significantly upregulated gene networks in lymphedema. Network analysis of the genes upregulated 2 and 6 weeks after surgery in comparison with control (unoperated) mice, according to RNA sequencing analysis, revealed a significant activation of inflammation- and T cell–related networks during lymphedema development (n = 5 per group per time point). RNA sequencing was performed once.
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