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Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema
Open accessAbstract
Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4 T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4 cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4 inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.
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“CD4+ T cells and cytokine signaling are critical to the regulation of fibrosis and swelling in the mouse tail wound model of lymphedema (140, 141).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [141]
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Metadata
- Authors
- Avraham, T., Zampell, J. C., Yan, A., Elhadad, S., Weitman, E. S., Rockson, S. G., Bromberg, J., & Mehrara, B. J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Division of Plastic and Reconstructive Surgery Department of Surgery New York New York USA
- Stanford Medicine (US)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2012-11-27
- Volume
- 27
- Issue
- 3
- Pages
- 1114-1126
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC3574290
- OpenAlex
- W2102471792
- Cited by
- 241
- References
- 42
- Citations by year
- 2026: 22 · 2025: 21 · 2024: 19 · 2023: 26 · 2022: 24 · 2021: 24 · 2020: 16 · 2019: 21 · 2018: 12 · 2017: 16 · 2016: 10 · 2015: 12 · 2014: 12 · 2013: 4
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (BC103691)
- National Heart, Lung, and Blood Institute
- National Institutes of Health (R01HL111130)
- Center for Scientific Review (P30 CA08748)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
- Keywords
- lymphedema, Th2 differentiation, fibrosis, lymphatic dysfunction, lymphatic stasis, IL-4, IL-13, lymphangiogenesis, cancer treatment complications, lymphedema treatment
- MeSH terms
- Animals, Cell Differentiation, Disease Models, Animal, Fibrosis, Inflammation, Lymphedema, Mice, Nude, Interleukin-4, Mice, Knockout, Th2 Cells, Interleukin-13, Mice
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