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Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema
Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA.;Chang Gung Univ, Chang Gung Mem Hosp, Div Reconstruct Microsurg, Dept Plast & Reconstruct Surg, Taoyuan, Taiwan..
Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168259Article in journal (Refereed) Published
Abstract [en]

Introduction Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. Methods We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later. Results LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses. Conclusions LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

Place, publisher, year, edition, pages
2016. Vol. 11, no 12, article id e0168259
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Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-316432DOI: 10.1371/journal.pone.0168259ISI: 000392745600059PubMedID: 27942023OAI: oai:DiVA.org:uu-316432DiVA, id: diva2:1077925
Funder
NIH (National Institute of Health), R01 HL111130-01 R21-CA194882 T32 CA9501-27 T32 CA9501-29
Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-11-29Bibliographically approved

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