title: Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.|Department of Plastic and Reconstructive Surgery, Division of Reconstructive Microsurgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jung-Ju
authors.initials: JJ
authors.lastname: Huang
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardenier
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Hespe
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Gabriela D
authors.initials: GD
authors.lastname: García Nores
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Raghu P
authors.initials: RP
authors.lastname: Kataru
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Catherine L
authors.identifier: http://orcid.org/0000-0003-1584-7258
authors.initials: CL
authors.lastname: Ly
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Inés
authors.initials: I
authors.lastname: Martínez-Corral
authors.affiliation: Transgenic Mice Unit, Biotechology Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000818:Animals; D006801:Humans; D008198:Lymph Nodes / Q000637:transplantation*; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels; D008209:Lymphedema / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology