title: Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.
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.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Epameinondas
authors.initials: E
authors.lastname: Gousopoulos
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Proulx
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Samia B
authors.initials: SB
authors.lastname: Bachmann
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Scholl
authors.affiliation: Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Dionyssiou
authors.affiliation: Department of Plastic Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Efterpi
authors.initials: E
authors.lastname: Demiri
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Halin
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Lothar C
authors.initials: LC
authors.lastname: Dieterich
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D042601:Lymphatic Vessels / Q000503:physiopathology*; D008209:Lymphedema / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse