T Cells are the primary source of TGF-β1 in lymphedema
Ira L. Savetsky, MD, Geoffrey E. Hespe, BS, Jason C. Gardenier, MD, Jeremy S. Torrisi, BA, Gabriela D. García Nores, MD, Seth Z. Aschen, BA, Dawit K. Jowhar, PhD, Matthew D. Nitti, BA, Raghu P. Kataru, PhD, Babak J. Mehrara, MD.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
We have shown previously that TGF-β1 plays a critical fibrogenic role in lymphedema. The purpose of this study was to determine the cellular source(s) of TGF-β1, understand the effects of TGF-β1 on lymphatic endothelial cells (LEC), and investigate the efficacy of a novel anti-TGF-β1 compound in preclinical mouse models of lymphedema.
We developed three distinct transgenic mice with selective knockout of TGF-β1 from T or myeloid cells, and a non-functional TGF-β receptor on LECs. These mice underwent microsurgical lymphatic ligation in the tail or popliteal lymphadenectomy. To study the efficacy of our novel anti-TGF-β1 compound, we compared this treatment with control mice after lymphatic injury.
TGF-β1 production was significantly decreased in T cell but not myeloid TGF-β1 knockout transgenic mice (50% reduction; P<0.01). Furthermore, TGF-β1 knockout T cell transgenic mice displayed decreased fibrosis, inflammation, and adipose deposition as compared to controls or TGF-β1 knockout myeloid mice. Blockade of TGF-β1 activity in LECs had no effect on the pathological changes of lymphedema but did increase lymphangiogenesis. Systemic or topical application of a novel anti-TGF-β1 compound decreased fibrosis, improved lymphatic function, and reversed the established swelling in the tail model.
We have shown for the first time that T cells are the primary source of TGF-β1 in lymphedema and that inhibition with a novel anti-TGF-β1 compound potently decreases tissue fibrosis after lymphatic injury. Furthermore, we have shown that the primary mechanism in which TGF-β1 causes lymphatic dysfunction is due to tissue fibrosis rather than direct effects on LECs.
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