Editors' ChoiceLYMPHEDEMA

T regulating lymphedema

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Science Translational Medicine  09 Nov 2016:
Vol. 8, Issue 364, pp. 364ec181
DOI: 10.1126/scitranslmed.aal0069

Secondary lymphedema associated with cancer therapy occurs in about 30% of breast cancer survivors, in addition to those treated for other malignancies. Lymphedema arises from lymphatic vessel injury and dysfunction, and patients afflicted with lymphedema suffer from swelling as a result of progressive functional impairment of their diseased limbs. Lymphedema causes a variety of morbidities that affect patient quality of life including physical discomfort, disfigurement, sensory deficits, recurrent inflammation, fibrosis, and impaired wound healing. The onset of lymphedema is often delayed by several years after cancer treatment, and though there is increasing evidence that chronic inflammation contributes to the pathogenesis, currently little is known about the mechanisms that underlie lymphedema development and no curative therapies exist.

To investigate the mechanisms involved in the development and progression of lymphedema, Gousopoulos et al. used a surgical mouse tail lymphedema model and RNA sequencing techniques to assess tissues at various times after surgical induction of disease. The team found enhancement of gene networks associated with regulatory T cells (Tregs) that play a role in immunological tolerance. Using immunohistochemistry, they also found high levels of infiltrating Tregs in both mouse and human lymphedema skin samples. Although the depletion of CD4+ cells was previously shown to decrease lymphedema, in the current study the specific depletion of Tregs—a functional subset of CD4+ cells—increased surgically induced mouse tail lymphedema development. Expansion of Tregs using interleukin-2 (IL-2) and anti–IL-2 antibody complexes prior to surgical induction of lymphedema reduced tail swelling in the mouse model. In a therapeutic model, the adoptive transfer of Tregs improved lymphatic functionality and lessened the hallmarks of lymphedema, including tissue swelling, inflammation, and fibrosis.

This study provides important mechanistic insight to the field of lymphatic research and biology in demonstrating a role for Tregs in influencing the onset and progression of secondary lymphedema. Although the clinical efficacy and feasibility remains to be established, this study suggests that adoptive cell therapy using Tregs represents a new therapeutic approach for the treatment of lymphedema.

E. Gousopoulos et al., Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function. JCI Insight 0.1172/jci.insight.89081 (2016). [Full Text]

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