Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.

Gousopoulos, Epameinondas; Proulx, Steven T; Bachmann, Samia B; Scholl, Jeannette; Dionyssiou, Dimitris; Demiri, Efterpi; Halin, Cornelia; Dieterich, Lothar C; Detmar, Michael (2016). Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function. JCI insight, 1(16), pp. 1-15. JCI Insight 10.1172/jci.insight.89081

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Proulx, Steven Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2379-3708

Publisher:

JCI Insight

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

21 Oct 2020 14:50

Last Modified:

21 Oct 2020 16:03

Publisher DOI:

10.1172/jci.insight.89081

PubMed ID:

27734032

BORIS DOI:

10.7892/boris.147214

URI:

https://boris.unibe.ch/id/eprint/147214

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