CD4+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis Journal Article


Authors: Zampell, J. C.; Yan, A.; Elhadad, S.; Avraham, T.; Weitman, E.; Mehrara, B. J.
Article Title: CD4+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis
Abstract: Introduction: Lymphedema is a chronic disorder that occurs commonly after lymph node removal for cancer treatment and is characterized by swelling, fibrosis, inflammation, and adipose deposition. Although previous histological studies have investigated inflammatory changes that occur in lymphedema, the precise cellular make up of the inflammatory infiltrate remains unknown. It is also unclear if this inflammatory response plays a causal role in the pathology of lymphedema. The purpose of this study was therefore to characterize the inflammatory response to lymphatic stasis and determine if these responses are necessary for the pathological changes that occur in lymphedema. Methods: We used mouse-tail lymphedema and axillary lymph node dissection (ANLD) models in order to study tissue inflammatory changes. Single cell suspensions were created and analyzed using multi-color flow cytometry to identify individual cell types. We utilized antibody depletion techniques to analyze the causal role of CD4+, CD8+, and CD25+ cells in the regulation of inflammation, fibrosis, adipose deposition, and lymphangiogenesis. Results: Lymphedema in the mouse-tail resulted in a mixed inflammatory cell response with significant increases in T-helper, T-regulatory, neutrophils, macrophages, and dendritic cell populations. Interestingly, we found that ALND resulted in significant increases in T-helper cells suggesting that these adaptive immune responses precede changes in macrophage and dendritic cell infiltration. In support of this we found that depletion of CD4+, but not CD8 or CD25+ cells, significantly decreased tail lymphedema, inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells significantly increased lymphangiogenesis both in our tail model and also in an inflammatory lymphangiogenesis model. Conclusions: Lymphedema and lymphatic stasis result in CD4+ cell inflammation and infiltration of mature T-helper cells. Loss of CD4+ but not CD8+ or CD25+ cell inflammation markedly decreases the pathological changes associated with lymphedema. In addition, CD4+ cells regulate lymphangiogenesis during wound repair and inflammatory lymphangiogenesis. © 2012 Zampell et al.
Keywords: controlled study; nonhuman; lymph node dissection; cd8+ t lymphocyte; animal cell; mouse; animal tissue; cell infiltration; dendritic cell; animal experiment; animal model; inflammation; immunoregulation; lymphangiogenesis; lymphedema; wound healing; fibrosis; regulatory t lymphocyte; cellular immunity; cd4+ t lymphocyte; innate immunity; adaptive immunity; cd25+ t lymphocyte; t cell depletion; macrophage; adipose tissue; helper cell; lymph flow; lipid storage
Journal Title: PLoS ONE
Volume: 7
Issue: 11
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2012-01-01
Start Page: e49940
Language: English
DOI: 10.1371/journal.pone.0049940
PROVIDER: scopus
PMCID: PMC3502174
PUBMED: 23185491
DOI/URL:
Notes: --- - "Export Date: 2 January 2013" - "Source: Scopus"
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MSK Authors
  1. Sonia Elhadad
    10 Elhadad
  2. Babak Mehrara
    295 Mehrara
  3. Tomer Avraham
    33 Avraham
  4. Jamie Christine Zampell
    29 Zampell
  5. Alan Yan
    20 Yan
  6. Evan Scott Weitman
    18 Weitman